Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation

ABSTRACT

The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor.

This application is a divisional of U.S. patent application Ser. No.11/914,919, filed May 20, 2008, now U.S. Pat. No. 7,923,465 which is theU.S. national phase of International Application No. PCT/IB2006/001437filed Jun. 1, 2006, which claims the benefit of Indian PatentApplication No. 659/MUM/2005 filed on Jun. 2, 2005, U.S. ProvisionalApplication No. 60/696,433, filed Jul. 1, 2005, Indian PatentApplication No. 1370/MUM/2005, filed Oct. 10, 2005, Indian PatentApplication No 344/MUM/2006, filed Mar. 9, 2006, U.S. ProvisionalApplication No. 60/744,071, filed Mar. 31, 2006 and Indian PatentApplication No. 689/MUM/2006, filed May 3, 2006, all of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel cannabinoid receptor modulators,in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptormodulators, and uses thereof for treating diseases, conditions and/ordisorders modulated by a cannabinoid receptor (such as pain,neurodegenative disorders, eating disorders, weight loss or control, andobesity).

BACKGROUND

The endogenous cannabinoid system comprises two main receptors, CB1 andCB2, and a number of ligands including anandamide and virodhamine whichdemonstrate the greatest activity at the cannabinoid receptor (JonathanA W & Louis J A, Obes Man., 5-19, 20f05). Anandamide, which is producedpostsynaptically, is the main fatty acid involved in the system. Itgains access to the extra cellular space and activates CB1 cannabinoidreceptors located on presynaptic nerve terminals. This activation causespresynaptic inhibition of γ-aminobutyric acid or glutamate throughinhibition of calcium channels, while simultaneously interfering withvesicle release and activating potassium channels.

However, anandamide is prone to rapid enzymatic hydrolysis. Thisrepresents a serious drawback in its use as a drug because, inter alia,substances which are susceptible to hydrolytic cleavage may undergochanges in the gastrointestinal tract.

CB1 receptors are predominantly located in the brain and other neurons,while CB2 receptors are predominantly located in immune cells.Stimulation of these receptors is known to affect the central andperipheral action on lipid and glucose metabolism in adipose tissue andmost notably, helps to regulate food intake, energy balance and nicotinedependence as well as regulate fear and anxiety.

There is evidence suggesting that CB1 agonists or antagonists,respectively, increase or decrease the motivation to work for palatableingesta (Gallate J E and McGregor I S, Psychopharmacology, 142, 302-308,1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur.J Pharmacol. 370, 233-240, 1999). Cannabinoids appear to directlystimulate eating by actions on appetitive processes, making food stimulimore salient and rapidly inducing eating even in satiated animals C Mand Kirkham T C, Physiol. Behan., 76, 241-250, 2002).

Current data reveals that cannabinoids mediate suppression ofinflammation in vitro and in vivo through stimulation of CB2 receptors(Ehrhart J, et. al. J. Neuroinflammation, 2, 29, 2005). The inflammatorymediators such as nitric oxide, cytokines, and chemokines play animportant role in microglial cell-associated neuron cell damage.Activated microglial cells have been implicated in a number ofneurodegenerative disorders, including Alzheimer's disease, multiplesclerosis, HIV and dementia.

Compounds capable of modulating the cannabinoid (CB) receptor activitycan be used in the treatment of CB receptor mediated syndromes, diseasesor disorders which include appetite, metabolism, diabetes, obesity,glaucoma associated intra-ocular pressure, mood disorders, seizures,substance abuse, learning disorders, cognition disorders, memorydisorders, organ contraction, muscle spasm, respiratory disorders,locomotor activity disorders, movement disorders, immune disorders,inflammation, cell growth disorders, eye-diseases, allergies andallergic reactions, pain, anxiety, psychotic afflictions, pathologicalstates of brain, gastrointestinal disorders, nausea, vomiting,giddiness, urinary and fertility problems, cardiovascular diseases,neuroinflammatory pathologies, diseases of the central nervous system,neurodegenerative syndromes, diseases and disorders, sleep disorders,dermatological disorders, leukocyte activation-associated disorder,autoimmune diseases, nephrological pathologies, delayed or immediatehypersensitivity, infectious parasitic, and viral and bacterialdiseases.

At present, various CB modulators have been Characterized as agonists,inverse agonists or antagonists to CB1 and/or CB2 receptors. Thesemodulators include naphthalen-1yl-(4-pentyloxy-naphthalen-1-yl)methanone(believed to be SAB-378),4-(2,4-dichlorophenylamino)-N-(tetrahydro-pyran-4-ylmethyl)-2-trifluromethyl-benzamide(GW-842166X), N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbox-amide (SR141716A),3-(4-chlorophenyl-N′-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide(SLV-319), and(R)-(+)-(2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthyl)methanone(WTN 55212-2).

These modulators have reached advanced stages of clinical trials for thetreatment of pain, neurodegenerative disorders, psychotic disorders,neurological syndromes, diseases or disorders, eating disorders,Alzheimer's disease, alcohol dependency, diabetes, obesity and/orsmoking cessation.

U.S. Pat. Nos. 5,624,941, 6,028,084, and 6,509,367, PCT Publication Nos.WO 98/31227, WO 98/41519, WO 98/43636 and WO 98/43635, and EuropeanPublication No. EP 0 658 546 disclose certain substituted pyrazoleshaving activity against the cannabinoid receptors. U.S. Pat. Nos.6,355,631 and 6,479,479 and PCT Publication Nos. WO 01/64632, 01/64633,and 01/64634 disclose certain azetidine derivatives, which arecannabinoid antagonists.

Other cannabinoid receptor modulating compounds are disclosed in U.S.Pat. Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, and5,532,237, and PCT Publication Nos. WO 97/29079, WO 98/37061, WO99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04/69837, WO04/058145, WO 04/26301, WO 04/058744, WO 04/096763 and WO06/030124.

There exists an unmet need for treatment of alcohol abuse. Health risksassociated with alcoholism include impaired motor control and decisionmaking, cancer, liver disease, birth defects, heart disease, drug/druginteractions, pancreatitis and interpersonal problems. Studies havesuggested that endogenous cannabinoid tone plays a critical role in thecontrol of ethanol intake. The endogenous. CB1 receptor antagonistSR-141716A has been shown to block voluntary ethanol intake in rats andmice. (See, Amone, M, et al., “Selective Inhibition of Sucrose andEthanol intake by SR141716, an Antagonist of Central Cannabinoid (CB1)Receptors,” Psychopharmacol, 132, 104-106 (1997)). For a review, see,Hungund, B. L and B. S. Basavarajappa, “Are Anadamide and CannabinoidReceptors involved in Ethanol Tolerance? A Review of the Evidence,”Alcohol & Alcoholism. 35(2) 126-133, 2000.

Current treatments for alcohol abuse or dependence generally suffer fromnon-compliance or potential hepatotoxicity. There is an unmet need formore effective treatments of alcohol abuse/dependence.

There also still exists a need for safer and more effective therapeutictreatments for diseases, conditions and/or disorders modulated bycannabinoid receptors (such as pain, obesity), including those modulatedby CB 1 or CB2 receptors.

SUMMARY OF INVENTION

The present invention relates to cannabinoid, receptor modulators of theformula:

and analogs thereof, pharmaceutically acceptable salts thereof,pharmaceutically acceptable esters thereof, tautomers thereof,regioisomers thereof, stereoisomers thereof, enantiomers thereof,diastereomers thereof, polymorphs thereof, and pharmaceuticallyacceptable solvates thereof,wherein

each of the dotted lines in formula (1) independently represents anoptional double bond;

U and V are independently C or N;

W, X and Y are independently C, N, O, S or —C(O)— with the proviso thatat least two of U, V, W, X or Y are independently selected from N, O,—C(O)— or S;

R, R¹ and R² may be same or different and are independently hydrogen,nitro, cyano, formyl, acetyl, halogen, —OR³, —SR³, oxo, thio,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, —NR³R⁴, —C(═B)—R³, —C(O)O—R³, —C(O)NR³R⁴,—S(O)_(m)—R³, —S(O)_(m)—NR³R⁴, or a protecting group or R¹ and R² may bejoined together to form an optionally substituted 3 to 7 memberedsaturated or unsaturated cyclic ring, which may optionally include atleast two heteroatoms selected from O, NR³ or S;

each occurrence of R³ and R⁴ may be same or different and areindependently hydrogen, nitro, halo, cyano, —OR^(a), —SR^(a), oxo, thio,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, —C(═B)—R^(a), —C(O)O—R^(a), —C(O)NR^(a)R^(b),—S(O)_(m)—R^(a), —S(O)_(m)—NR^(a)R^(b), —NR^(a)R^(b), or a protectinggroup or R³ and R⁴, when bound to a common atom, may be joined togetherto form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring, which may optionally include at least twoheteroatoms selected from O, NR³ or S;

each occurrence of R^(a) and R^(b) may be same or different and areindependently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo,thio, —C(O)—R^(c), —C(O)O—R^(c), —C(O)NR^(c)R^(d), —S(O)_(m)—R^(c),—S(O)_(m)—NR^(c)R^(d), —NR^(c)R^(d), —OR^(c), —SR^(c), a protectinggroup, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyl alkyl, or substituted or unsubstitutedheteroarylalkyl;

each occurrence of R^(c) and R^(d) may be same or different and areindependently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo,thio, a protecting group, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, or substituted or unsubstituted heteroaryl alkyl;

each occurrence of B is independently O, S or NR³;

p and m are independently 0, 1 or 2;

A is

wherein:

each of the dotted lines in A independently represents an optionaldouble bond;

R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are independentlyhydrogen, nitro, cyano, formyl, acetyl, halogen, —OR¹⁵, —SR¹⁵, oxo,thio, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, —NR¹⁵R¹⁶, —C(═B)—R¹⁵, —C(O)O—R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(m)—R¹⁵, —S(O)_(m)—NR¹⁵R¹⁶, or a protecting group;

R⁵ and R⁶ may be joined together to form an optionally substituted 3 to11 membered saturated or unsaturated mono or bicyclic ring, which mayoptionally include at least one heteroatom selected from O, NR³ or S;

R⁹ and R¹⁰ may be joined together to form an optionally substituted 3 to11 membered saturated or unsaturated mono or bicyclic ring, which mayoptionally include at least one heteroatom selected from O, NR³ or S;

R⁵ and R⁹ may be joined together to form an optionally substituted 3, to11 membered saturated or unsaturated mono or bicyclic ring, which mayoptionally include at least one heteroatom selected from O, NR³ or S;

R⁷ and R¹⁰ may be joined together to form an optionally substituted 3 to11 membered saturated or unsaturated mono or bicyclic ring, which mayoptionally include at least one heteroatom selected from O, NR³ or S;

each occurrence of R¹⁵ and R¹⁶ may be same or different and areindependently hydrogen, nitro, halo, cyano, —OR³, —SR³, oxo, thio,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic group, substituted or unsubstitutedheterocyclylalkyl, —C(═B)—R³, —C(O)O—R³, —C(O)NR³R⁴, —S(O)_(m)—R³,—S(O)_(m)—NR³R⁴, —NR³R⁴ or R¹⁵ and R¹⁶, when bound to a common atom, maybe joined together to form an optionally substituted 3 to 7 memberedsaturated or unsaturated cyclic ring, which may optionally include atleast two heteroatoms selected from O, NR³ or S wherein R³ and R⁴ are asdefined as above;

n is 1, 2, 3, or 4; and

a, b, c, d and e are integers independently selected from 0 to 4, withthe proviso that the modulator does not have the formula:

wherein R¹ and R² are as defined above.

Preferred is a compound of general formula (1) wherein U and V are C.

Further preferred is where Y and X are N, and W is C.

Further preferred is where 13 in the —C(B)NR¹R² group is O.

Further preferred is where R is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl.

Further preferred is where R is methyl, phenyl, 2-chlorophenyl,4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl,4-fluorophenyl, 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl,2-(4-chlorophenyl)phenyl or 5-chloropyridin-2-yl.

Further preferred is where R¹ is hydrogen.

Further preferred is where R² is substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heterocyclicgroup, substituted or unsubstituted heteroaryl group, substituted orunsubstituted heteroarylalkyl, or NR³R⁴.

Further preferred is where R² is t-butyl, n-pentyl, cyclopentyl,cyclohexyl, adamantan-1-yl, 2-methyladamantan-2-yl,3-hydroxyadamantan-1-yl, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,1-phenyl cyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl,4-chlorophenyl, 3-bromophenyl, 2-methoxyphenyl, 4-tert-butylphenyl,2,4-difluorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl,2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl,2,6-difluorobenzyl, 2-bromobenzyl, 4-bromobenzyl,4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl,2-phenylethyl, 1-(2-chlorophenyl)ethyl, 2(4-fluorophenyl)ethyl,1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1-(2-chlorophenyl)1-methylethyl,methylphenylethanoate, 2-hydroxy-1-phenylethyl, piperidinyl,morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl,3-pyridylmethyl, or 4-pyridylmethyl.

Further preferred is where R¹ and R² are joined together to form anoptionally substituted 3 to 7 membered saturated or unsaturated cyclicring, which may optionally include at least two heteroatoms selectedfrom O, NR³ or S.

Further preferred is where R¹ and R² together with nitrogen atom towhich are they are bound form piperidin-1-yl or morpholinyl (e.g.,morpholin-1-yl).

Further preferred is where R² is NR³R⁴; wherein each occurrence of R³and R⁴ may be same or different and are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or R³ and R⁴ are joined together to form anoptionally substituted 3 to 7 membered saturated or unsaturated cyclicring, which may optionally include at least two heteroatoms selectedfrom O, NR³ or S.

Further preferred is where R³ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl or substituted or unsubstitutedcycloalkyl.

Further preferred is where R³ is methyl, phenyl or cyclohexyl.

Further preferred is where R⁴ is selected from substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl orsubstituted or unsubstituted cycloalkyl.

Further preferred is where R⁴ is phenyl, 2-chlorophenyl, 4-chlorophenyl,2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-bromophenyl,3-chloropyridin-2-yl, 5-chloropyridin-2-yl, or cyclohexyl.

Further preferred is where R² is —NR³R⁴, wherein R³ and R⁴ are joinedtogether to form an optionally substituted 3 to 7 membered saturated orunsaturated cyclic ring, which may optionally include at least twoheteroatoms selected from O, NR³ or S;

Further preferred is where R³ and R⁴ are joined together to formpiperidin-1yl or morpholin-4-yl.

Further preferred is where A is

wherein

R⁵ to R¹⁴ are independently hydrogen or methyl; and

R⁸ is substituted or unsubstituted phenyl.

Further preferred is where R⁸ is 4-chlorophenyl.

Further preferred is where a=b=c=d=e=1.

More preferably, U and V are C, X and Y are N, W is —C(O)NR¹R².

Further preferred is p=1.

According to one embodiment, when A is 1,7,7trimethyl-bicyclo[2.2.1]heptane and p is 1, then R does not representunsubstituted phenyl.

According to one preferred embodiment, Y is N, U is C, one of W, V, andX is N and the remaining two are C, B in the group —C(B)NR¹R² is O, andA, R, R¹, and R² are as defined above.

Another embodiment is a cannabinoid receptor modulator of Formula 1A,

or an analog thereof, pharmaceutically acceptable salt thereof,pharmaceutically acceptable ester thereof, tautomer thereof, regioisomerthereof, stereoisomer thereof, enantiomer thereof, diastereomer thereof,polymorph thereof, or pharmaceutically acceptable solvate thereof,wherein

R, R¹ and R² may be same or different and are independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclic group, substituted or unsubstitutedheteroaryl group or substituted or unsubstituted heteroarylalkyl or R¹and R² may be joined together to form an optionally substituted 3 to 7membered saturated or unsaturated cyclic ring, which may optionallyinclude at least two heteroatoms selected from O, NR³ or S. or NR³R⁴;

each occurrence of R³ and R⁴ may be same or different and areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or substituted or unsubstitutedheterocyclic group or R³ and R⁴ may be joined together to form anoptionally substituted 3 to 7 membered saturated or unsaturated cyclicring, which may optionally include at least two heteroatoms selectedfrom O, NR³ or S;

p is 1; and

A is

wherein

each of the dotted lines in A independently represents an optionaldouble bond, and

each occurrence of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ isthe same or different and selected from hydrogen, substituted orunsubstituted alkyl or substituted or unsubstituted aryl;

with the proviso that the modulator does not have the formula:

wherein R¹ and R² are as defined above.

According to one embodiment, when A is 1,7,7trimethyl-bicyclo[2.2.1]heptane and p is 1, then R does not representunsubstituted phenyl.

According to one preferred embodiment, R is substituted or unsubstitutedaryl.

Further preferred is where R is aryl substituted with halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyor substituted or unsubstituted aryl.

Further preferred is where R is 2-chlorophenyl, 4-chlorophenyl,2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl,2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl or2-(4-chlorophenyl)phenyl.

Further preferred is where R is 2,4-dichlorophenyl or2,4-difluorophenyl.

Another preferred embodiment is a cannabinoid receptor modulator ofFormula I(a) to I(g),

wherein R, R¹, R² and R⁸ are as defined above and R in formula 1(c) isnot unsubstituted phenyl.

According to one preferred embodiment, R is a phenyl group substitutedwith at least one halogen atom. More preferably, R is a phenyl groupsubstituted with one or two halogen atoms (e.g., 2,4-difluorophenyl or2,4-dichlorophenyl).

Yet another embodiment is a selective CB2 agonist (i.e., a CB2 agonistthat does not substantially inhibit or activate the CB1 receptor) havingthe formula:

wherein R, R¹, and R² are as defined above. R is preferably asubstituted or unsubstituted aryl, more preferably substituted orunsubstituted phenyl, and even more preferably a substituted phenyl.Even more desirably, R is a phenyl group substituted with one or twohalogen atoms (e.g., 2,4-difluorophenyl or 2,4-dichlorophenyl). Thesecompounds are particularly useful in the treatment of disorders mediatedby agonizing the CB2 receptor, including, but not limited to, ophthalmicdiseases, respiratory disorders, immune disorders (such as autoimmunedisorders), inflammation, pain (such as neuropathic pain) andneurodegenerative related syndromes. Accordingly, the present inventionalso includes methods of treating any of these disorders in a subject inneed thereof by administering a therapeutically effective amount of oneor more compounds of formula 1(b).

Representative compounds of the present invention listed below areillustrative in nature only and do not limit to the scope of theinvention.

-   101.    N(7)-Piperidino-5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4    (8),6-diene-7-arboxamide,-   102.    N(7)-Benzyl-5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   103.    N(7)-Morpholino-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   104.    N(7)-(3-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   105.    N(7)-(4-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   106.    N(7)-Cyclohexyl-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   107.    N(7)-(N-cyclohexyl-N-methylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   108.    N(7)-Cyclohexylmethyl-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   109.    N(7)-(Adamantan-1-yl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   110. N(7)-(1S,2    endo-1,3,3-Trimethyl-bicyclo[2.2.1]hept-2-yl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   111.    N(7)-(2-Chlorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   112.    N(7)-(4-Chlorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   113.    N(7)-(4-Fluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   114.    N(7)-(2,4-Difluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   115.    N(7)-(2,6-Difluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   116.    N(7)-(4-Trifluoromethylbenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   117.    N(7)-(1-Phenylethyl))-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   118.    N(7)-(R-1-Phenylethyl))-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   119.    N(7)-(1-Methyl-1-phenylethyl))-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   120.    N(7)-(2-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   121.    N(7)-(N′-phenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   122.    N(7)-(N′-phenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide    hydrochloride,-   123.    N(7)-(2-Chlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   124.    N(7)-(2-Chlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,    hydrochloride,-   125.    N(7)-[(4-chlorophenyl)amino)]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   126.    N(7)-(2,4-Dichlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   127.    N(7)-[(2,4-Dichlorophenyl-N′-methylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   128.    N(7)-[(2,4-Dichlorophenyl-N′-methylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide    hydrochloride,-   129.    N(7)-(2,4-Dichlorophenyl-N′-cyclohexylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   130,    N(7)-(4-fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   131.    N(7)-(4-Fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide    hydrochloride,-   132.    N(7)-(2,4-Difluorophenylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   133.    N(7)-(3-fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   134.    N(7)-(3-Chloro-2-pyridylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   135.    N(7)-(5-Chloro-2-pyridylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   136.    N(7)-(2-Phenylethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   137.    N(7)-(N′,N′-Diphenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   138.    N(7)-[1-(2-Chlorophenyl)ethyl]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   139.    N(7)-Benzyl-5-(4′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4    (8)-6-diene-7-carboxamide,-   140.    N(7)-Piperidino-5-(4′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   141.    7-(4′-Chlorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-dien-5-yl-piperidinomethanone,-   142.    N(7)-Phenyl-5-(4′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4    (8)-6-diene-7-carboxamide,-   143.    N(7)-Piperidino-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   144.    N(7)-(Adamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   145. N(7)-(1S,2endo-1,3,3-Trimethyl-bicyclo[2.2.1]hept-2    (2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   146.    N(7)-(S-1-phenylethyl))-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   147.    N(7)-(R-1-phenylethyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   148.    N(7)-(1-Methyl-1-phenylethyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   149.    N(7)-(2-Chlorobenzyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4    (Y), 6-diene-7-carboxamide,-   150.    N(7)-(2,4-Dichlorophenylamino)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   151.    N(7)-[1-(2-Chlorophenyl)ethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4    (8),6-diene-7-carboxamide,-   152.    N(7)-[(5)-1-Phenylpropyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   153.    N7-[1-(2-Chlorophenyl)-1-methylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   154.    Methyl(2R)-2-[7-(2,4-difluorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),5-dien-5-ylcarboxamido]-2-phenylethanoate,-   155.    Methyl(2S-2-[7-(2,4-difluorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),5-dien-5-ylcarboxamido]-2-phenylethanoate,-   156.    N7-(3-Hydroxyadamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   157.    N(7)-(1-Methyl-1-phenylethyl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   158.    N(7)-(Adamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   158a.    N7-(Adamantan-2-yl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   159.    N7-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   160.    N(7)-Piperidino-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   161.    N(7)-(2,4-Dichlorophenylamino)-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   162.    N(7)-(2-Chlorobenzyl)-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   163.    N(7)-Piperidino-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   164.    N7-(2-Chlorobenzyl)-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   165.    N(7)-(2,4-Dichlorophenylamino)-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   166.    N(7)-Piperidino-5-[(2-chlorophenyl)phenyl]-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   167.    N(7)-[(2,4-Dichlorophenyl)amino]-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   168.    N(7)-Phenyl-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   169.    N(7)-piperidino-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   170.    N(7)-Benzyl-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   171.    N(7)-phenyl-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-dien-5-yl-piperidinomethanone,-   172.    N(7)-(4-Fluorobenzyl)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   173.    N(7)-Phenylamino-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   174.    N(7)-(2-Chlorophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]-4(8),6-diene-7-carboxamide,-   175.    N(7)-(2,4-Dichlorophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   176.    N(7)-(2-Bromophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   177.    N(7)-(N′,N′-Diphenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   178.    N(7)-(2-Phenylethyl)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   179.    N(7)-Benzyl-5-(2′,4′-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   180.    N(7)-piperidino-5-(2′,4′-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   181.    N(7)-(2,4-Dichlorophenylamino)-5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   182.    N(7)-Benzyl-5-(2′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   183.    N(7)-cyclohexyl-5-(2′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   184.    N(7)-piperidino-5-(2′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   185.    N7-(2-Chlorobenzyl)-5-(5-chloro-2-pyridyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   186.    N(7)-Benzyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   187.    N(7)-piperidino-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   188.    6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-dien-5-yl-piperidinomethanone,-   189a    N(7)-piperidino-6-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   189b    N(7)-piperidino-5-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   190a    N(7)-(1-methyl-1-phenylethyl)-6-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4,7-diene-7-carboxamide,-   190b    N(7)-(1-methyl-1-phenylethyl)-5-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide,-   191.    N(7)-[(1R)-2-Hydroxy-1-phenylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   192.    N(7)-[(1S-2-Hydroxy-1-phenylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   201.    N(3)-Piperidino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   202.    N(3)-Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   203.    N(3)-Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   204.    N(3)-Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   205.    N(3)-Piperidino-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   206.    N(3)-Cyclohexyl-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   207.    N(3)-Benzyl-1(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   208.    N(3)-Phenylamino-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   209.    N(3)-Piperidino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   210.    1-(4-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazol-3-yl    piperidino methanone,-   211.    N(3)-Cyclohexyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   212.    N(3)-Cyclopentyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   213.    N(3)-[(N-Cyclohexyl-N-methyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   214.    N(3)-Phenyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   215.    N(3)-(3-Chlorophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   216.    N(3)-(4-Chlorophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   217.    N(3)-(3-Bromophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   218.    N(3)-(2-Methoxyphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   219.    N(3)-(4-tert-Butylphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   220.    N(3)-Benzyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   221.    N(3)-(2-Chlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   222.    N(3)-(4-Chlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   223.    N(3)-(2,4-Dichlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   224.    N(3)-(2-Bromobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   225.    N(3)-(4-Bromobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   226.    N(3)-(4-Fluorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   227.    N(3)-(4-Trifluoromethylbenzyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   228.    N(3)-Phenylamino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   229.    N(3)-[(4-Chlorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   230.    N(3)-[(2,4-Dichlorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   231.    N(3)-[(3,4-Dichlorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   232.    N(3)-[2-Fluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   233.    N(3)-[(3-Fluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   234.    N(3)-[(4-Fluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   235.    N(3)-[(2,4-Difluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   236.    N(3)-(N′,N′-Diphenylamino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   237.    N(3)-Cyclohexyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   238.    N(3)-Cyclohexylmethyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   239.    N(3)-(N,N-Dicyclohexylamino)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   240.    N(3)-(4H-1,2,4-triazol-4-yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   241. N(3)-(1,3,3-Trimethyl    bicyclo[2.2.1]hept-2-yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   242.    N(3)-(Adamantan-1-yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   243.    N(3)-Phenyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   244.    N(3)-(2,4-Difluorophenyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   245.    N(3)-(2-Fluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   246.    N(3)-(4-Fluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   247.    N(3)-(2,4-Difluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   248.    N(3)-(2,6-Difluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   249.    N(3)-(2-Chlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   250.    N(3)-(4-Chlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   251.    N(3)-(2,4-Dichlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   252.    N(3)-[S-(1-phenylethyl)]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   253.    N(3)-[R-(1-phenylethyl)]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,    methano-indazole-3-carboxamide,-   254.    N(3)-(2-phenylethyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   255.    N(3)-[2-(2,4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   256.    N(3)-Phenylamino-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   257.    N(3)-[(2-Chlorophenyl)-amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   258.    N(3)-[N-(2-Chlorophenyl)-N-methylamino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   259.    N(3)-[(4-Chlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   260.    N(3)-[(2,4-Dichlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-1-4,7-methano-indazole-3-carboxamide,-   261.    N(3)-[(2,4-dichlorophenyl)-N-methylamino]-1-(2,4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   262.    N(3)-[(3,4-Dichlorophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   263.    N(3)-[(2-Bromophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-methano-indazole-3-carboxamide,-   264.    N(3)-[(2-Fluorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   265.    N(3)-[(2,4-Difluorophenyl)amino]-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   266.    N(3)-[(3-Fluorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   267.    N(3)-[(3-chloropyridin-2-yl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   268.    N(5)-piperidino-3-(2′-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide;-   269.    N(5)-benzyl-3-(2′-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   270.    N(3)-Piperidino-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   271.    N(3)-Cyclohexyl-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   272.    N(3)-Benzyl-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   273.    N(3)-Phenylamino-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   274.    N(3)-Piperidino-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   275.    N(3)-Cyclohexyl-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   276.    N(3)-Benzyl-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   277.    N(3)-Phenylamino-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   278.    N(3)-[(2-Fluorophenyl)amino]-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   279.    N(3)-Cyclohexyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   280.    N(3)-Benzyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxyamide,-   281. N5-(Adamantan-2-yl)-3-(4-fluorophenyl)-3,4-diaza    tricyclo[5.2.1.0^(2,6)]deca-2 (6),4-diene-5-carboxamide,-   282.    N5-(1-Methyl-1-phenylethyl)-3-(4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   283.    N5-(Adamantan-1-yl)-3-(4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   284.    N(3)-Phenylamino-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   285.    N(3)-Phenylamino-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   286.    N(3)-[(2-Chlorophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   287.    N(3)-[(2-bromophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   288.    N(3)-[(2-Fluorophenyl)amino]-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   289.    N(3)-Piperidino-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   290.    N(3)-Cyclohexyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   291.    N(3)-(Cyclohexylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   292.    N(3)-[S-(1-Phenylethyl)]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   293.    N(3)-(R-1-phenylethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   294.    N(3)-(1-Methyl-1-phenylethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   295.    N5-[1-(2-Chlorophenyl)-1-methylethyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   296.    N(3)-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   297.    N5-(2-Chlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   298.    N5-(4-Chlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   299.    N5-(1-Ethyl-1-phenylpropyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   300.    N5-[(1S)-1-Phenylpropyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   301.    Methyl(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]-2-phenylethanoate,-   302.    N5-[(1S)-2-Hydroxy-1-phenylethyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   303.    N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   304. (4S,7S) or    (4S,7R)—N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   305. (4S,7R) or    (4R,7S)—N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   306.    N5-n-Pentyl-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   307.    N5-(2,4-Dichlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   308.    N5-(1-phenylcyclopropyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   309.    N5-(2-Adamantyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   310.    N5-(2-Methyl-2-adamantyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide,-   311N7-(3-Hydroxyadamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide,-   312.    4-[5-(2,4-Difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]morpholine,-   313.    N(3)-(tert-Pentyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   314.    N(3)-Cyclopropanmethyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   315.    N(3)-Cyclobutyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   316.    N(3)-(Tetrahydro-2H-4-pyranmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   317.    N(3)-Cyclopropyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   318.    N(3)-(4-methylpiperazino)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   319.    Methyl(2R)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2    (6),3-dien-3-ylcarboxamido]-2-phenylethanoate,-   320.    N(3)-[(1R)-2-Hydroxy-1-phenylethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   321.    N(3)-(tert-Butyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   322.    N(3)-(Tetrahydro-2-furanylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   323.    N(3)-(tert-Butyl)-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   324.    N(3)-(tert-Butyl)-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   325.    N(3)-(tert-Butyl)-1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   326.    Methyl(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]-2-(4-fluorophenyl)ethanoate,-   327.    N(3)-(tert-Butyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   328.    N(3)-(4-Hydroxyphenyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   329.    N(3)-(tert-Butyl)-1-(2-ethoxy,4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   330.    N(3)-(2-furylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   331.    N(3)-(2-thiophenemethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   332.    N(3)-[(1S)-2-Hydroxy-1-(4-fluorophenyl)ethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   333.    Methyl-(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2    (6),3-dien-3-ylcarboxamido]-4-methylpentanoate:-   334.    N(3)-(Adamantan-1yl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   335a    N(3)-(tert-butyl)-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   335b    N(3)-(tert-butyl)-2-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   336a    N(3)-(tert-butyl)-1-(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   336b    N(3)-(tert-butyl)-2-(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide:-   337.    N(3)-(2-hydroxyethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   338.    N(3)-(Thienylethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   339.    N(3)-(Isopropyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   340.    N(3)-[(1S)-2-Methoxy-1-phenylethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   401.    N(3)-Phenyl-1-(2,4-dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   402.    N(3)-[(2-Fluorophenyl)amino]-1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   403.    N(3)-[(2,4-Difluorophenyl)amino]-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   404.    N(3)-[(3-chloropyridin-2-yl)amino]-1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   405.    N(3)-(Adamantan-1-yl)-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   406.    N(3)-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   407.    N(3)-(1-Methyl-1-phenylethyl))-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   408.    (4R,7S)—N(3)-tert-Butyl-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methano-indazole-3-carboxamide,-   409. Methyl    (2R)-2-[1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamido]-2-phenylethanoate,-   410.    N(3)-[(1R-2-Hydroxy-1-phenylethyl]-1-(2,4-difluorophenyl)-7,8,8-trimethyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,-   411.    (4S,7R)—N(3)-tert-Butyl-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methano-indazole-3-carboxamide,-   412.    N(3)-pentyl-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methano-indazole-3-carboxamide-   501.    N(12)-Benzyl-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   502.    N(12)-Piperidino-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   503.    N(12)-Piperidino-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,    hydrochloride,-   504.    N(12)-[(N′-Cyclohexyl-N′-methyl)amino]-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,6,9(13),    11-pentaene-12-carboxamide,-   505.    N(12)-{N′-[(2,4-Dichlorophenyl)-N′-methyl]amino}-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   506.    N(12)-(Adamantan-1yl)-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   507.    N12-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2(7),3,5,9(13),11-pentaene-12-carboxamide,-   508.    N12-(1-Methyl-1-phenylethyl)-10-(2,4,dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   509.    N12-(1-Methyl-1-phenylethyl)-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   601.    N(12)-Benzyl-16-(4-chlorophenyl)-10-(2,4-dichlorophenyl)-15,17-dioxo-10,11,16-triazapentacyclo[6.5.2.0^(2,7).0^(9,13).0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   602.    N(12)-Piperidino-16-(4-chlorophenyl)-10-(2,4-dichlorophenyl)-15,17-dioxo-10,11,16-triazapentacyclo[6.5.2.0^(2,7).0^(9,13).0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   701.    N12-Benzyl-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   702.    N(12)-tert-Butyl-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   703.    N12-(1-Methyl-1-phenylethyl)-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxamide,-   801.    N5-(tert-Butyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]undeca-2(6),4-diene-5-carboxamide,-   802.    N(5)-(tert-Pentyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]undeca-2(6),4-diene-5-carboxamide.

I(a)

Example No. R R¹ R² 101

H

102

H

103

H

104

H

105

H

106

H

107

H

108

H

109

H

110

H

111

H

112

H

113

H

114

H

115

H

116

H

117

H

118

H

119

H

120

H

121

H

 122*

H

123

H

 124*

H

125

H

126

H

127

H

 128*

H

129

H

130

H

 131*

H

132

H

133

H

134

H

135

H

136

H

137

H

138

H

139

H

140

H

141

142

H

143

H

144

H

145

H

146

H

147

H

148

H

149

H

150

H

151

H

152

H

153

H

154

H

155

H

156

H

157

H

158

H

 158a

159

H

160

H

161

H

162

H

163

H

164

H

165

H

166

H

167

H

168

H

169

H

170

H

171

172

H

173

H

174

H

175

H

176

H

177

H

178

H

179

H

180

H

181

H

182

H

183

H

184

H

185

H

186 H H

187 H H

188 H

 189b CH₃I H

 190b

H

191

H

192

H

I(aa)

Example no R R₁ R₂ 189a CH₃ H

190a

H

*Indicates HCl salt

TABLE (Ib)

Example No. R R₁ R₂ 201

H

202

H

203

H

204

H

205

H

206

H

207

H

208

H

209

H

210

211

H

212

H

213

H

214

H

215

H

216

H

217

H

218

H

219

H

220

H

221

H

222

H

223

H

224

H

225

H

226

H

227

H

228

H

229

H

230

H

231

H

232

H

233

H

234

H

235

H

236

H

237

H

238

H

239

H

240

H

241

H

242

H

243

H

244

H

245

H

246

H

247

H

248

H

249

H

250

H

251

H

252

H

253

H

254

H

255

H

256

H

257

H

258

H

259

H

260

H

261

H

262

H

263

H

264

H

265

H

266

H

267

H

268

H

269

H

270

H

271

H

272

H

273

H

274

H

275

H

276

H

277

H

278

H

279

H

280

H

281

H

282

H

283

H

284

H

285

H

286

H

287

H

288

H

289

H

290

H

291

H

292

H

293

H

294

H

295

H

296

H

297

H

298

H

299

H

300

H

301

H

302

H

303

H

304

H

305

H

306

H

307

H

308

H

309

H

310

H

311

H

312

H

313

H

314

H

315

H

316

H

317

H

318

H

319

H

320

H

321

H

322

H

323

H

324

H

325

H

326

H

327

H

328

H

329

H

330

H

331

H

332

H

333

H

334

H

 335a

H

 336a

H

337

H

338

H

339

H

340

H

I(bb)

Example No. R R₁ R₂   335b

H

336b

H

TABLE (1c)

Example No. R R₁ R₂ 401

H

402

H

403

H

404

H

405

H

406

H

407

H

408

H

409

H

410

H

411

H

412

H

TABLE (1d)

Example No. R R₁ R₂ 501

H

502

H

 503*

H

504

H

505

H

506

H

507

H

508

H

509

H

TABLE (1e)

Example No. R R₁ R₂ 601

H

602

H

TABLE I(f)

Example No. R R¹ R² 701

H

702

H

703

H

TABLE (1g)

Example No. R R¹ R²   801

H

802

H

Another embodiment of the invention is a pharmaceutical compositioncomprising at least one compound of the present invention and apharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition comprises a therapeutically effective amount of thecompound(s) of the present invention.

Yet another embodiment is a method for preventing, ameliorating ortreating a cannabinoid receptor mediated disease, disorder or syndrome(such as a disease, disorder or syndrome mediated by interaction withthe CB1 or CB2 receptor) in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound of the present invention.

Such conditions include, but are not limited to, appetite disorders,metabolism disorders, catabolism disorders, diabetes, obesity,ophthalmic diseases, social related disorders, mood disorders, seizures,substance abuse, learning disorders, cognition disorders, memorydisorders, organ contraction, muscle spasm, respiratory disorders,disorders and diseases, locomotor activity disorders, movementdisorders, immune disorders (such as autoimmune disorders),inflammation, cell growth, pain and neurodegenerative related syndromes.

A preferred condition is pain, ophthalmic diseases, respiratorydisorders, immune disorders (such as autoimmune disorders),inflammation, cell growth, and neurodegenerative related syndromes.

Yet another embodiment is a method for preventing, ameliorating ortreating an appetite disorder, social related disorder, autoimmune orinflammation, pain or neurodegenerative related syndrome, disorder ordisease, or substance abuse, in a subject in need thereof byadministering to the subject a therapeutically effective amount of acompound of the present invention.

Yet another embodiment is a method for preventing, ameliorating ortreating an appetite related disease, disorder or syndrome, such asobesity, an overweight condition, anorexia, bulimia, cachexia,dysregulated appetite, an obesity related syndrome, disorder, disease orsymptom (including, but not limited to, obesity as a result of genetics,diet, food intake volume, metabolic syndrome, disorder or disease,hypothalmic disorder or disease, age, abnormal adipose massdistribution, abnormal adipose compartment distribution, a compulsiveeating disorder, or a motivational disorder which includes the desire toconsume sugars, carbohydrates, alcohols or drugs or any ingredient withhedonic value, and/or reduced activity) in a subject in need thereof byadministering to the subject a therapeutically effective amount of acompound of the present invention.

Yet another embodiment is a method for preventing, ameliorating ortreating a social related disease, disorder or syndrome, including, butnot limited to, depression and its types, bipolar depression, unipolardepression, single or recurrent major depressive episodes with orwithout psychotic features, catatonic features, melancholic features,atypical features or postpartum onset, seasonal affective disorder,dysthymic disorders with early or late onset and with or withoutatypical features, neurotic depression and social phobia, depressionaccompanying dementia, anxiety, psychosis, social affective disorders,and/or cognitive disorders, in a subject in need thereof byadministering to the subject a therapeutically effective amount of acompound of the present invention.

Yet another embodiment is a method for preventing, ameliorating ortreating an autoimmune or inflammation related disease, disorder orsyndrome, including, but not limited to, psoriasis, lupus erythematosus,diseases of the connective tissue, Sjögren's syndrome, ankylosingspondylarthritis; rheumatoid arthritis, reactional arthritis,undifferentiated spondylarthritis, Behcet's disease, autoimmunehemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis,amyloses, graft rejection or diseases affecting the plasma cell line,allergic diseases (such as delayed or immediate hypersensitivity,allergic rhinitis, contact dermatitis or allergic conjunctivitisinfectious parasitic), viral or bacterial diseases (such as AIDS andmeningitis), inflammatory diseases (such as diseases of the jointsincluding, but not limited to, arthritis, rheumatoid arthritis,osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease,inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) andosteoporosis in a subject in need thereof by administering to thesubject a therapeutically effective amount of a compound of the presentinvention.

Yet another embodiment is a method for preventing, ameliorating ortreating pain or a neurodegenerative related syndrome, disorder ordisease, including, but not limited to, central and peripheral pathwaymediated pain, bone and joint pain, migraine headache associated pain,cancer pain, dental pain, menstrual cramps, labor pain, chronic pain ofthe inflammatory type, pain associated with allergies, rheumatoidarthritis, dermatitis or immunodeficiency, chronic neuropathic pain(including pain associated with diabetic neuropathy, sciatica, nonspecific lower back pain, fibromyalgia, and HIV-related neuropathy),post herpetic neuralgia, trigeminal neuralgia, pain resulting fromphysical trauma, amputation, cancer, toxins or chronic inflammatoryconditions, Hodgkin's disease, myasthenia gravis, nephrotic syndrome,scleroderma and thyroiditis, in a subject in need thereof byadministering to the subject a therapeutically effective amount of acompound of the present invention.

Yet another embodiment is a method for preventing, ameliorating ortreating a substance abuse related syndrome, disorder or diseaseincluding, but not limited to, drug abuse and drug withdrawal in which,for example, the substance of abuse or dependence is alcohol,amphetamines, amphetamine like substances, caffeine, cannabis, cocaine,hallucinogens, inhalants, opioids, nicotine (and/or tobacco products),heroin abuse, barbiturates, phencyclidine (or phencyclidine-likecompounds), sedative-hypnotics, benzodiazepines, or combinations ofsubstances of abuse, in a subject in need thereof by administering tothe subject a therapeutically effective amount of a compound of thepresent invention.

Yet another embodiment is a method for reducing tobacco craving in asubject in need thereof by administering to the subject atherapeutically effective amount of a compound of the present invention.

Yet another embodiment is a method for treating nicotine dependency,addiction, withdrawal or aiding in the cessation or lessening of tobaccouse in a subject in need thereof by administering to the subject atherapeutically effective amount of a compound of the present invention.

Yet another embodiment is a method of preparing a compound of formula(1), where Y is N, U is C, one of W, V, and X is N and the remaining twoare C, B is O, and A, R, R¹, R² and p are as defined above. The methodincludes the step of coupling an amine of the formula HNR¹R² with acompound of the formula:

wherein L² is a leaving group, to form the compound of formula (1).

Yet another embodiment is a method of preparing a compound of formula(1), where W and Y are N, U, V, and X are C, B is O, and A, R, R¹, R²and p are as defined above. The method includes the steps of:

-   -   (a) oxidizing a compound of formula K:

to yield a compound of formula B:

-   -   (b) subjecting the compound of formula B to reductive amination        to form the vicinal diamine of formula C:

-   -   (c) monoacylating the vicinal diamine of formula C to form a        mono N-acyl diamine of formula D:

wherein pg is a protecting group;

-   -   (d) subjecting the compound of formula D to cyclization to form        a compound of formula E:

-   -   (e) dehydrogenating the compound of formula E to form a compound        of formula F:

-   -   (f) derivatizing the compound of form F to form compound G1,        compound G2, or a mixture thereof:

-   -   (g) hydrolyzing compound. G1, compound G2, or both to form        compound H1, compound H2, or both:

and

-   -   (h) coupling an amine of the formula HNR¹R² with compound H1,        compound H2, or both to form the compound of formula (1).

Yet another embodiment is a method of preparing a compound of formula(1), where X and Y are N, U, V, and W are C, B is O, and A, R, R¹, R²and p are as defined above. The method includes the steps of:

-   -   (a) deprotonating a compound of formula K:

followed by acylation to yield a compound of formula L:

-   -   (b) reacting the compound of formula L with a hydrazine having        the formula RNHNH₂ to form compound M, compound N, or both:

and

-   -   (c) hydrolyzing and coupling compound M, compound N, or both        with an amine of the formula HNR¹R² to form the compound of        formula (1).

Yet another embodiment is a method of preparing a compound of formula(1), where V and Y are N, U, W, and X are C, B is O, p is 0 or 1, and A,R, R¹ and R² are as defined above. The method includes the steps of:

-   -   (a) converting a compound of formula O:

to a compound of formula P:

-   -   (b) coupling compound P with an amine of the formula Q:

to form a compound of formula R:

-   -   (c) deprotecting the compound of formula R followed by        condensation to form a compound of formula S:

and

-   -   (d) hydrolyzing and coupling the compound of formula S with an        amine of the formula HNR¹R² to form the compound of formula (1).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph of the mean percent reversal of neuropathichyperalgesia(±SEM) as measured by the Seltzer model (protocol V) 0.5 and1 hour after dosing with vehicle, 100 mg/kg gabapentin, or 0.01, 0.1,0.3, or 1 mg/kg of the compound of Example 294.

FIG. 2 is a bar graph of the mean percent reversal of neuropathichyperalgesia (±SEM) as measured by the chronic constriction injury tosciatic nerve model (protocol VI) 0.5 and 1 hour after dosing withvehicle, 100 mg/kg gabapentin, or 0.1 mg/kg of the compound of Example294.

FIG. 3 is a bar graph of the mean percent of maximum possible analgesia(MPE) (±SEM) as measured by the tail-flick method (protocol VII) 1, 3,6, 12, and 18 hours after dosing with vehicle, 3 mg/kg (i.p.) WIN55212-2, or 0.3, 1, or 3 mg/kg (i.p.) of the compound of Example 294.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “aryl” refers to aromatic radicals having 6 to 14 carbon atomssuch as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15-membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from nitrogen, phosphorus, oxygen and sulfur. For purposes ofthis invention, the heterocyclic ring radical may be a monocyclic,bicyclic or tricyclic ring system, which may include fused, bridged orspino ring systems, and the nitrogen, phosphorus, carbon, oxygen orsulfur atoms in the heterocyclic ring radical may be optionally oxidizedto various oxidation states. In addition, the nitrogen atom may beoptionally quaternized; and the ring radical may be partially or fullysaturated (i.e., heterocyclic or heteroaryl). Examples of suchheterocyclic ring radicals include, but are not limited to, azetidinyl,acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl,cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl,pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl,triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl,thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure.

The term “heteroaryl” refers to an aromatic heterocyclic ring radical.The heteroaryl ring radical may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directlybonded to an alkyl group. The heteroarylalkyl radical may be attached tothe main structure at any carbon atom from the alkyl group that resultsin the creation of a stable structure.

The term “heterocyclyl” refers to a heterocyclic ring radical as definedabove. The heterocyclyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radicaldirectly bonded to an alkyl group. The heterocyclylalkyl radical may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched chainhaving 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl,2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and2-butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond, and having 2 toabout 12 carbon atoms (with radicals having 2 to about 10 carbon atomsbeing preferred), e.g., ethynyl, propynyl, and butynyl.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkageto the rest of the molecule. Representative examples of such groups are—OCH₃ and —OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude, but are not limited to, perhydronaphthyl, adamantyl andnorbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g.,sprio(4,4)non-2-yl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radical,having 3 to about 8 carbon atoms, directly attached to an alkyl group.The cycloalkylalkyl group may be attached to the main structure at anycarbon atom in the alkyl group that results in the creation of a stablestructure. Non-limiting examples of such groups includecyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term “cycloalkylaryl” refers to a cyclic ring-containing radical,having 3 to about 8 carbon atoms, directly attached to an aryl groupNon-limiting examples of such groups include phenylcyclopropyl,phenylcyclobutyl and phenylcyclopentyl.

The term “cycloalkenyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms with at least one carbon-carbon doublebond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

Unless otherwise specified, the term “substituted” as used herein refersto substitution with any one or any combination of the followingsubstituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedamino, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclylalkyl ring,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, substituted or unsubstituted guanidine,—COOR_(x), —C(O)R_(x), —C(S)R^(x), —C(O)NR_(x)R_(y), —C(O)ONR_(x)R_(y),—NR_(x)CONR_(y)R_(z), —N(R_(x))SOR_(y), —N(R_(x))S O₂R_(y),—(═N—N(R_(x))R_(y)), —NR_(x)C(O)OR_(y), —NR_(x)R_(y), —NR_(x)C(O)R_(y),—NR_(x)C(S)R_(y), —NR_(x)(S)NR_(y)R_(z), —SONR_(x)R_(y),—SO₂NR_(x)R_(y), —OR_(x), —OR_(x)C(O)NR_(y)R_(z), —OR_(x)C(O)OR_(y),—OC(O)R_(x), —OC(O)NR_(x)R_(y), —R_(x)NR_(y)C(O)R_(z), —R_(x)OR_(y),—R_(x)C(O)OR_(y), —R_(x)C(O)NR_(y)R_(z), —R_(x)C(O)R_(y),—R_(x)OC(O)R_(y), —SR_(x), —SOR_(x), —SO₂R_(x), and —ONO₂, whereinR_(x), R_(y) and R_(z) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl, or substituted or unsubstitutedheterocyclic ring. According to one embodiment, the substituents in theaforementioned “substituted” groups cannot be further substituted. Forexample, when the substituent on “substituted alkyl” is “substitutedaryl” the substituent on “substituted aryl” cannot be “substitutedalkenyl”.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The term “cannabinoid receptor” refers to any one of the known orheretofore unknown subtypes of the class of cannabinoid receptors,including CB1 and/or CB2 receptors, that may be bound by a cannabinoidmodulator compound of the present invention.

The term “modulator” further refers to the use of a compound of theinvention as a CB (e.g., CB1 and/or CB2) receptor agonist, partialagonist, antagonist or inverse-agonist.

The term “treating” or “treatment” of a state, disorder or conditionincludes:

-   -   (1) preventing or delaying the appearance of clinical symptoms        of the state, disorder or condition developing in a subject that        may be afflicted with or predisposed to the state, disorder or        condition but does not yet experience or display clinical or        subclinical symptoms of the state, disorder or condition;    -   (2) inhibiting the state, disorder or condition, i.e., arresting        or reducing the development of the disease or at least one        clinical or subclinical symptom thereof; or    -   (3) relieving the disease, i.e., causing regression of the        state, disorder or condition or at least one of its clinical or        subclinical symptoms.

The benefit to a subject to be treated is either statisticallysignificant or at least perceptible to the subject or to the physician.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn), salts of organic bases (such asN,N′-diacetylethylenediamine, glucamine, triethylamine, choline,hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, andthiamine), salts of chiral bases (such as alkylphenylamine, glycinol,and phenyl glycinol), salts of natural amino acids (such as glycine,alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine,cysteine, methionine, proline, hydroxy proline, histidine, ornithine,lysine, arginine, and serine), salts of non-natural amino acids (such asD-isomers or substituted amino acids), salts of guanidine, salts ofsubstituted guanidine (Wherein the substituents are selected from nitro,amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammoniumsalts, and aluminum salts. Other pharmaceutically acceptable saltsinclude acid addition salts (where appropriate) such as sulphates,nitrates, phosphates, perchlorates, borates, hydrohalides, acetates(such as trifluoroacetate), tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.Yet other pharmaceutically acceptable salts include, but are not limitedto, quaternary ammonium salts of the compounds of invention with alkylhalides or alkyl sulphates (such as MeI or (Me)₂SO₄).

Pharmaceutically acceptable solvates includes hydrates and othersolvents of crystallization (such as alcohols). The compounds of thepresent invention may form solvates with standard low molecular weightsolvents by methods known in the art.

Pharmaceutical Compositions

The pharmaceutical composition of the present invention comprises atleast one compound of the present invention and a pharmaceuticallyacceptable excipient (such as a pharmaceutically acceptable carrier ordiluent). Preferably, the pharmaceutical composition comprises atherapeutically effective amount of the compound(s) of the presentinvention. The compound of the present invention may be associated witha pharmaceutically acceptable excipient (such as a carrier or a diluent)or be diluted by a carrier, or enclosed within a carrier which can be inthe form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylatedcastor oil, peanut oil, olive oil, gelatin, lactose, terra alba,sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose,magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid orlower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acidamines, fatty acid monoglycerides and diglycerides, pentaerythritolfatty acid esters, polyoxyethylene, hydroxymethyl cellulose andpolyvinylpyrrolidone.

The carrier or diluent may include a sustained release material, such asglyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or morepharmaceutically acceptable auxiliary agents, wetting agents,emulsifying agents, suspending agents, preserving agents, salts forinfluencing oxmetic pressure, buffers, sweetening agents, flavoringagents, colorants, or any combination of the foregoing. Thepharmaceutical composition of the invention may be formulated so as toprovide quick, sustained, or delayed release of the active ingredientafter administration to the subject by employing methods known in theart.

The pharmaceutical compositions of the present invention may be preparedby conventional techniques, e.g., as described in Remington: The Scienceand Practice of Pharmacy, 20^(th) Ed., 2003 (Lippincott Williams &Wilkins). For example, the active compound can be Mixed with a carrier,or diluted by a carrier, or enclosed within a carrier, which may be inthe form of an ampoule, capsule, sachet, paper, or other container. Whenthe carrier serves as a diluent, it may be a solid, semi-solid, orliquid material that acts as a vehicle, excipient, or medium for theactive compound. The active compound can be adsorbed on a granular solidcontainer, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, forexample, capsules, tablets, aerosols, solutions, suspensions or productsfor topical application.

The route of administration may be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action. Suitable routes of administration include, butare not limited to, oral, nasal, pulmonary, buccal, subdermal,intradermal, transdermal, parenteral, rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmic (suchas with an ophthalmic solution) or topical (such as with a topicalointment). The oral route is preferred.

Solid oral formulations include, but are not limited to, tablets,capsules (soft or hard gelatin), dragees (containing the activeingredient in powder or pellet form), troches and lozenges. Tablets,dragees, or capsules having talc and/or a carbohydrate carrier or binderor the like are particularly suitable for oral application. Preferablecarriers for tablets, dragees, or capsules include lactose, cornstarch,and/or potato starch. A syrup or elixir can be used in cases where asweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tablettingtechniques may contain: (1) Core: Active compound (as free compound orsalt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mgmicrocrystalline cellulose (Avicel®), 70 mg modified cellulose gum(Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx.0.9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride

Liquid formulations include, but are not limited to, syrups, emulsions,soft gelatin and sterile injectable liquids, such as aqueous ornon-aqueous liquid suspensions or solutions.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Methods of Treatment

The present invention provides compounds and pharmaceutical formulationsthereof that are useful in the treatment, amelioration, and/orprevention of diseases, conditions and/or disorders modulated by acannabinoid (CB) receptor, especially those modulated by the CB1 or CB2receptor including those discussed below.

The present invention further provides a method of treating a disease,condition and/or disorder modulated by a cannabinoid receptor (CB), andin particular the CB1 or CB2 receptor, in a subject in need thereof byadministering to the subject a therapeutically effective amount of acompound or a pharmaceutical composition of the present invention.

Diseases, conditions, and/or disorders that are modulated by a CBreceptor, include, but are not limited to, appetite disorders,metabolism disorders, catabolism disorders, diabetes, obesity, socialrelated disorders, mood disorders, seizures, substance abuse, learningdisorders, cognition disorders, memory disorders, organ contraction,muscle spasm, respiratory disorders, locomotor activity disorders,movement disorders, immune disorders (such as autoimmune disorders),inflammation, cell growth, pain (such as neuropathic pain) andneurodegenerative related syndromes, disorders and diseases.

Appetite related syndromes, disorders or diseases include, but are notlimited to, obesity, overweight conditions, anorexia, bulimia, cachexia,dysregulated appetite and the like. Obesity related syndromes, disordersor diseases include, but are not limited to, obesity as a result ofgenetics, diet, food intake volume, metabolic syndrome, disorder ordisease, hypothalmic disorder or disease, age, abnormal adipose massdistribution, abnormal adipose compartment distribution, compulsiveeating disorders, motivational disorders which include the desire toconsume sugars, carbohydrates, alcohols or drugs or any ingredient withhedonic value and the like. Symptoms associated with obesity relatedsyndromes, disorders, and diseases include, but are not limited to,reduced activity.

Metabolism related syndromes, disorders or diseases include, but are notlimited to, metabolic syndrome, dyslipidemia, elevated blood pressure,insulin sensitivity or resistance, hyperinsulinemia,hypercholesterolemia, hyperlipidemias, atherosclerosis,hypertriglyceridemias, arteriosclerosis, other cardiovascular diseases,osteoarthritis, dermatological diseases, sleep disorders (disturbancesof circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy),cholelithiasis, hepatomegaly, steatosis, abnormal alanineaminotransferase levels, polycystic ovarian disease, inflammation, andthe like.

Diabetes related syndromes, disorders or diseases include, but are notlimited to, glucose dysregulation, insulin resistance, glucoseintolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity,hyperglycemia and the like.

Catabolism related syndromes, disorders or diseases include, but are notlimited to, catabolism in connection with pulmonary dysfunction andventilator dependency; cardiac dysfunction, e.g., associated withvalvular disease, myocardial infarction, cardiac hypertrophy orcongestive heart failure.

Ophthalmic diseases include, but are not limited to, glaucoma,glaucoma-associated intraocular pressure retinitis, retinopathies,uveitis, acute injury to the eye tissue (e.g. conjunctivitis).

Social or mood related syndromes, disorders or diseases include, but arenot limited to, depression (including, but not limited to, bipolardepression, unipolar depression, single or recurrent major depressiveepisodes with or without psychotic features, catatonic features,melancholic features, atypical features or postpartum onset, seasonalaffective disorder, dysthymic disorders with early or late onset andwith or without atypical features, neurotic depression and socialphobia, depression accompanying dementia, anxiety, psychosis, socialaffective disorders, cognitive disorders and the like).

Substance abuse related syndromes, disorders or diseases include, butare not limited to, drug abuse and drug withdrawal. Abused substancesinclude, but are not limited to, alcohol, amphetamines (or amphetaminelike substances), caffeine, cannabis, cocaine, hallucinogens, inhalants,opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates,phencyclidine (or phencyclidine-like compounds), sedative-hypnotics,benzodiazepines, or combinations of any of the foregoing. The compoundsand pharmaceutical compositions can also be used to treat withdrawalsymptoms and substance-induced anxiety or mood disorder.

The present invention further provides a method of treating nicotinedependency, addiction, withdrawal or aiding in the cessation orlessening of tobacco in a subject in need thereof by administering tothe subject a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Learning, cognition or memory related syndromes, disorders or diseaseswhich can be treated with the compounds of the present inventioninclude, but are not limited to, memory loss or impairment as a resultof age, disease, side effects of medications (adverse events) or thelike. Memory impairment is a primary symptom of dementia and can also bea symptom associated with such diseases as Alzheimer's disease,schizophrenia, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and headtrauma as well as age-related cognitive decline. Generally, dementiasare diseases that include memory loss and additional intellectualimpairment separate from memory. The compounds and pharmaceuticalcompositions of the present invention are also useful in treatingcognitive impairments related to attentional deficits, such as attentiondeficit disorder.

Muscle spasm syndromes, disorders or diseases include, but are notlimited to, multiple sclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseasesinclude, but are not limited to, stroke, Parkinson's disease, multiplesclerosis, epilepsy and the like.

Respiratory related syndromes, disorders or diseases include, but arenot limited to, diseases of the respiratory tract, chronic obstructivepulmonary disorder, emphysema, asthma, bronchitis and the like.

Kidney dysfunction nephritis which can be treated with the modulators ofthe present invention include, but is not limited to, mesangialproliferative glomerulonephritis, nephritic syndrome, liver dysfunction(hepatitis, cirrhosis).

Autoimmune or inflammation related syndromes, disorders or diseasesinclude, but are not limited to, psoriasis, lupus erythematosus,diseases of the connective tissue, Sjögren's syndrome, ankylosingspondylarthritis, rheumatoid arthritis, reactional arthritis,undifferentiated spondylarthritis, Behcet's disease, autoimmunehemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis,amyloses, graft rejection or diseases affecting the plasma cell line;allergic diseases: delayed or immediate hypersensitivity, allergicrhinitis, contact dermatitis or allergic conjunctivitis infectiousparasitic, viral or bacterial diseases (such as AIDS and meningitis),inflammatory diseases (such as diseases of the joints including, but notlimited to, arthritis, rheumatoid arthritis, osteoarthritis,spondylitis, gout, vasculitis, Crohn's disease, inflammatory boweldisease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis.

Cell growth related syndromes, disorders or diseases include, but arenot limited to, dysregulated mammalian cell proliferation, breast cancercell proliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include, but are notlimited to, central and peripheral pathway mediated pain, bone and jointpain, migraine headache associated pain, cancer pain, dental pain,menstrual cramps, labor pain, chronic pain of the inflammatory type,allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronicneuropathic pain, (e.g. pain associated with diabetic neuropathy,sciatica, non specific lower back pain, fibromyalgia; HIV-relatedneuropathy; post herpetic neuralgia, trigeminal neuralgia, and painresulting from physical trauma, amputation, cancer, toxins or chronicinflammatory conditions), hodgkin's disease, myasthenia gravis,nephrotic syndrome, scleroderma, thyroiditis and the like.

Neurodegenerative related syndromes, disorders or diseases include, butare not limited to, Parkinson's disease, multiple sclerosis, epilepsy,ischemia or secondary biochemical injury collateral to traumatic head orbrain injury, brain inflammation, eye injury or stroke and the like.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include, but are not limited to,anti-obesity agents such as apolipoprotein-B secretion/microsomaltriglyceride transfer protein (apo-B/MTP) inhibitors, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD type 1) inhibitors, peptide YY₃₋₃₆ oranalogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists,monoamine reuptake inhibitors (such as sibutramine), sympathomimeticagents, β₃ adrenergic receptor agonists, dopamine receptor agonists(such as bromocriptine), melanocyte-stimulating hormone receptoranalogs, 5HT_(2c) receptor agonists, melanin concentrating hormoneantagonists, leptin (the OB protein), leptin analogs, leptin receptoragonists, galanin antagonists, lipase inhibitors (such astetrahydrolipstatin, i.e. orlistat), anorectic agents (such as abombesin agonist), neuropeptide-Y receptor antagonists, thyromimeticagents, dehydroepiandrosterone or an analog thereof, glucocorticoidreceptor agonists or antagonists, orexin receptor antagonists,glucagon-like peptide-1 (GLP-1) receptor agonists, Protein TyrosinePhosphatase (PTP-1B) inhibitors, dipeptidyl peptidase IV (DPP-IV)inhibitors, ciliary neurotrophic factors (such as Axokine™ availablefrom Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y. and Procter &Gamble Company, Cincinnati, Ohio), human agouti-related protein (AGRP)inhibitors, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists.Other anti-obesity agents, including the preferred agents set forthherein below, are well known, or will be readily apparent in light ofthe instant disclosure, to one of ordinary skill in the art.

Especially preferred are anti-obesity agents such as orlistat,sibutramine, bromocriptine, ephedrine, leptin, peptide YY₃₋₃₆ or ananalog thereof (including the complete peptide YY), and pseudoephedrine.Preferably, compounds of the present invention and combination therapiesare administered in conjunction with exercise and a sensible diet.

Anti-obesity agents for use in the combinations, pharmaceuticalcompositions, and methods of the invention can be prepared using methodsknown to one of ordinary skill in the art, for example, sibutramine canbe prepared as described in U.S. Pat. No. 4,929,629; bromocriptine canbe prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888;orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143,5,420,305, 5,540,917, and 5,643,874; and PYY₃₋₃₆ (including analogs) canbe prepared as described in U.S. Patent Publication No. 2002/0141985 andInternational Publication No. WO 03/027637. All of the above recitedreferences are incorporated herein by reference.

Other suitable pharmaceutical agents that may be administered incombination with the compounds of the present invention include agentsdesigned to treat tobacco abuse (e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban™)and nicotine replacement therapies), agents to treat erectiledysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHDagents (e.g., Ritalin™ (methylphenidate hydrochloride), Strattera™(atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride)and Adderall™ (amphetamine aspartate; amphetamine sulfate;dextroamphetamine saccharate; and dextroamphetamine sulfate)), andagents to treat alcoholism, such as opioid antagonists (e.g., naltrexone(also known under the tradename ReVia™) and nalmefene), disulfiram (alsoknown under the tradename Antabuse™), and acamprosate (also known underthe tradename Campral™)). In addition, agents for reducing alcoholwithdrawal symptoms may also be co-administered, such asbenzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin™). Treatment for alcoholism is preferablyadministered in combination with behavioral therapy including suchcomponents as motivational enhancement therapy, cognitive behavioraltherapy, and referral to self-help groups, including Alcohol Anonymous(AA).

Other pharmaceutical agents that may be useful include antihypertensiveagents; antidepressants (e.g., fluoxetine hydrochloride (Prozac™));cognitive improvement agents (e.g., donepezil hydrochloride (Aircept™)and other acetylcholinesterase inhibitors); neuroprotective agents(e.g., memantine); antipsychotic medications (e.g., ziprasidone(Geodon™), risperidone (Risperdal™), and olanzapine (Zyprexa™)); insulinand insulin analogs (e.g., LysPro insulin); GLP-1 (7-37)(insulinotropin) and GLP-1 (7-36)-NH₂; sulfonylureas and analogsthereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide,acetohexamide, Glypizide®, glimepiride, repaglinide, meglitinide;biguanides: metformin, phenformin, buformin; α2-antagonists andimidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan,fluparoxan; other insulin secretagogues: linogliride, A-4166;glitazones: ciglitazone, Actos™ (pioglitazone), englitazone,troglitazone, darglitazone, Avandia® (BRL49653); fatty acid oxidationinhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;β-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243;phosphodiesterase inhibitors: L-386,398; lipid-lowering agents:benfluorex: fenfluramine; vanadate and vanadium complexes (e.g.,Naglivan®) and peroxovanadium complexes; amylin antagonists; glucagonantagonists; gluconeogenesis inhibitors; somatostatin analogs;antilipolytic agents: nicotinic acid, acipimox, WAG 994, pramlintide(Symlin™), AC 2993, nateglinide, aldose reductase inhibitors (e.g.,zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenaseinhibitors, sodium-hydrogen exchanger type 1 (NHE-1) inhibitors and/orcholesterol biosynthesis inhibitors or cholesterol absorptioninhibitors, especially a HMG-CoA reductase inhibitor, or a HMG-CoAsynthase inhibitor, or a HMG-COA reductase or synthase gene expressioninhibitor, a CETP inhibitor, a bile acid sequesterant, a fibrate, anACAT inhibitor, a squalene synthetase inhibitor, an anti-oxidant orniacin. The compounds of the present invention may also be administeredin combination with a naturally occurring compound that acts to lowerplasma cholesterol levels. Such naturally occurring compounds arecommonly called nutraceuticals and include, for example, garlic extract,Hoodia plant extracts, and niacin.

The compounds of the present invention (including the pharmaceuticalcompositions and processes used therein) may be used alone or incombination with other pharmaceutical agents in the manufacture of amedicament for the therapeutic applications described herein.

General Method of Preparation

The compound of general formula (1) can be synthesized by the schemesillustrated below.

The compounds of formula (1), wherein W and Y are N; U, V and X are C; Bis O; p is 0 or 1; and R, R¹ and R² are as described in the generaldescription, can be synthesized as shown in scheme 1.

In the above scheme, the compound of general formula K may be oxidised(for example, with SeO₂ (selenium dioxide)) to give a compound ofgeneral formula B, which may then be subjected to reductive amination(e.g., under standard conditions (e.g., hydrogenation in the presence ofNH₄OAc, Pd/C)) to obtain the vicinal diamine of general formula C.Compound C may be monoacylated (e.g., with an acid chloride of theformula pgOCH₂COCl or an anhydride of the formula (pgOCH₁₂)CO (whereinpg is an alcohol protecting group, e.g., benzyl or methoxymethyl (MOM)))to obtain a mono N-acyl diamine of general formula D. The compound ofgeneral formula D can be subjected to intramolecular cyclisation to givecompound E. Compound E can be dehydrogenated (e.g., using an oxidizingagent (such as ceric ammonium nitrate or2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ))) to yield the compoundof general formula F. Compound F is converted to compounds G1 and/or G2.For example, derivatisation of compound F by acylaytion, alkylation orarylation would provide compounds of general formula G1 and/or G2 whichmay be separated. The compound of general formula G1 and/or G2 thusobtained can be hydrolysed to form compound(s) 11.1 and/or 112.Compounds H1 and/or H2 can be coupled with an amine (e.g., HNR¹R²) toform a compound of formula (1). Suitable amines include, but are notlimited to, N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) andbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP) reagent.

In another embodiment, the compounds of the formula (1) wherein X and Yare N; U, V and W are C; B is O; p is 0 or 1; R, R¹ and R² are asdescribed in the general description, can be synthesized as shown inscheme 2.

In the above scheme, the compound of general formula K can bedeprotonated, e.g., using a base (such as LiHMDS or LDA), followed byacylation, e.g., using diethyl oxalate, to obtain compound of generalformula L. The compound of general formula L can be then treated with asubstituted hydrazine (such as RNHNH₂) to obtain the compound(s) ofgeneral formula M and/or N. The compound(s) of general formula M and/orN thus obtained can be hydrolysed and coupled with an amine (e.g.,HNR¹R²) to form a compound of formula (1). Suitable amines include, butare not limited to, N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) andbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(BOP) reagent.

In yet another embodiment, the compounds of the formula (1) wherein Vand Y are nitrogen; U, W and X are carbon; B is oxygen; p is 0 or 1 andR, R¹ and R² are as described in the general description, can besynthesized as shown in scheme 3.

In the above scheme, the compound of general formula O is converted to acompound of general formula P. Compound P is then coupled with an amineof the general formula Q, for example, thermally or catalysed byreagents such as Hg(OAc)₂, to form a compound of the general formula R.Compound R is deprotected and condensed to form a compound of thegeneral formula S. The deprotection and subsequent intramolecularcondensation of compound. R is preferably performed in the presence ofan acid (such as p.TsOH, MsOH, TfOH or CF₃COOH). The compound of generalformula S can be hydrolysed and coupled with an amine (e.g., HNR¹R²) toform a compound of formula (1). Suitable amines include, but are notlimited to, N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) andbenzotriazol-1-yloxytris(dimethylamine)-phosphonium hexafluorophosphate(HOP) reagent.

It is to be understood that the present invention encompasses allisomers of compounds of formula (I) and their pharmaceuticallyacceptable derivatives, including all geometric, tautomeric 10 andoptical forms, and mixtures thereof (e.g. racemic mixtures). Whereadditional chiral centres are present in compounds of formula (I), thepresent invention includes within its scope all possiblediastereoisomers, including mixtures thereof. The different isomericforms may be separated or resolved one from the other by conventionalmethods, or any given isomer may be obtained by conventional syntheticmethods or by stereospecific or asymmetric syntheses. The subjectinvention also includes isotopically-labeled compounds, which areidentical to those recited in formulas I and following, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, iodine, 20 and chlorine such as ³H, ¹¹C, ¹⁴C,¹⁸F, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable saltsof the compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., 14C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e, 2H, canafford 30 certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates or solvates as well as compounds containing variable amounts ofwater and/or solvent.

Embodiments of the present invention are illustrated by the followingexamples. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of these examples, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

EXPERIMENTAL SECTION

Abbreviations and notations: The following abbreviations and notationshave been used in the following text. M.P.: melting point. BOP reagent:(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate. FC: Flash Chromatography. J: Coupling constantsexpressed in units of Hz. THF: tetrahydrofuran. Et₃N: triethyl amine.BuLi: butyl lithium. LiHMDS: lithium hexamethyl disilazide

Intermediate 15-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl 2-oxo-(5-oxotricyclo[4.3.1.1.^(3,8)]undec-4-yl)acetate

A 1.6M soln. of n-BuLi in hexane was added to a solution ofhexamethyldisilazane (1.27 ml, 5.4 mmol) in diethyl ether (10.0 ml) at−78° C. and stirred at that temperature for 15 min. To this mixture wasadded a solution of homoadamantanone [900 mg, 5.4 mmol, preparedaccording to: Black, R. M. and Gill, G. B., J. Chem. Soc. (C), 1970,671] in diethyl ether (27.0 ml) and stirring at −78° C. was continuedfor further 45 min. Diethyl oxalate (0.98 ml, 6.5 mmol) was added andthe mixture was allowed to slowly warm up to 25° C. After stirringovernight, water (25 ml) was added to the solution and the layersseparated. The aqueous layer was washed twice with diethyl ether (20ml), acidified with 1N HCl and extracted into diethyl ether (3×20 ml),the organic layer was dried over Na₂SO₄, filtered and evaporated. Flashchromatography (petroleum ether/ethyl acetate 97:3) gave the titlecompound as a yellow oil (589 mg, 36%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz):15.75 (s, 1H); 4.33 (q, J=7.2, 2H); 2.80 (br. t, J=6, 1H); 2.75-2.70 (m,1H); 2.13-85 (m, 8H); 1.81-1.69 (m, 4H); 1.36 (m, t, J=7.2, 3H). IR(cm⁻¹ neat): 3423 (br.), 2982 (w), 2919 (s), 2851 (m), 1741 (s), 1599(s, br.).

Step 2: Ethyl5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

A solution of intermediate 1 (2.0 g, 7.56 mmol), 2-bromophenylhydrazinehydrochloride (1.86 g, 8.32 mmol) and ethanol (30 ml) was refluxed for 1h. After cooling, the precipitated solid was collected by filtration anddried to give the title product in pure form (2.04 g, 65%). ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.67 (dd, J=7.8, 1.2, 1H); 7.42-7.26 (m, 3H); 4.40(q, J=7.2, 2H); 3.79 (br. t, J=5.4, 1H); 2.54 (br. t, J=7.2, 1H); 2.18(br. s, 2H); 2.14-1.92 (m, 4H); 1.92-1.60 (m, 6H); 1.39 (t, J=7.2, 3H).

Step 3:5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

A solution of Ethyl5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylatein ethanol:water (20:1) was refluxed with KOH (270 mg, 4.82 mmol) for 2h. After removal of ethanol, the residue was dissolved in water andacidified to pH 4.0 with aqueous IN HCl. The precipitate was filteredand dried to give pure intermediate 1 (715 mg, 77%) was obtained. ¹H-NMR(δ ppm, CDCl₃, 300, MHz): 7.71 (dd, J=7.8, 1.5, 1H); 7.50-7.32 (m, 3H);3.79 (br. t, J=5.1, 1H); 2.56 (br. t, J=5.0, 1H); 2.19 (s, 2H);2.12-1.90 (m, 4H); 1.90-1.66 (m, 6H).

The intermediates 2 to 11 were prepared according to the process asdescribed in step 2 & 3 of intermediate 1, using Ethyl2-oxo-(5-oxotricycle[4.3.1.1.^(3,8)]undec-4-yl)acetate, appropriate(un)substituted phenyl or pyridyl hydrazine and alkali

Intermediate 25-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(4chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 54%, ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.43, 7.30 (AB, J=10, 4H);4.40 (q, J=7.5, 2H); 3.79 (t, J=5.1, 1H); 3.0 (t, J=5.4, 1H); 2.21 (br.s, 2H); 2.06-1.77 (m, 1.0H); 1.40 (t, J=7.5, 3H).

Step 2:5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 89%. ¹H-NMR (δ ppm, DMSO-d₆): 7.59 (d, J=8.7, 2H); 7.39 (d,J=8.7, 2H); 3.76 (br. s, 1H); 2.97 (br. s, 1H); 2.14 (br. s, 2H);1.67-1.98 (m, 10H).

Intermediate 35-(2,4-Difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(2,4-Difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 96%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.40 (m, 1H); 7.02-6.90(m, 2H); 4.38 (q, J=7.2, 2H); 3.76 (br. s, 1H); 2.66 (br. s, 1H); 2.17(br. s, 2H); 2.05-1.70 (m, 10H), 1.37 (t, J=7.2, 3H).

Step 2:5-(2,4-Difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 95%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 12.80 (br. s, 1H); 7.70-7.55(m, 2H); 7.30 (br. t, J=7.5, 1H); 3.66 (br. s, 1H); 2.63 (br. s, 1H);2.13 (s, 2H); 2.00-1.71 (m, 10H).

Intermediate 45-(4-Fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(4-Fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 55%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.38-7.31 (m, 2H); 7.18-7.11(m, 2H); 4.39 (q, J=7.5, 2H); 3.78 (br. s, 1H); 2.95 (br. s, 1H); 2.20(br. s, 2H); 2.06-1.76 (m, 10H); 1.39 (t, J=7.2, 3H).

Step 2:5-(4-Fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 81%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.60 (br. s, 1H);7.47-7.35 (m, 4H); 3.67 (br. s, 1H); 2.91 (br. s, 1H); 2.14 (br. s, 2H);1.98-1.71 (m, 10H).

Intermediate 55-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 91%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.23 (s, 4H); 4.39 (q,J=7.2, 2H); 3.79 (br. t, J=5.7, 1H); 3.00 (br. s, (H); 2.41 (s, 3H);2.19 (br. s, 2H); 2.07-1.95 (m, 2H); 1.95-1.73 (m, 8H); 1.40 (t, J=7.2,3H).

Step 2:5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 99%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.60 (br. s, 1H); 7.34(d, J=8.1, 2H); 7.26 (d, J=8.1, 2H); 3.68 (br. s, 1H); 2.94 (br. s, 1H);2.37 (s, 3H); 2.12 (br. s, 2H); 2.05-1.62 (m, 10H).

Intermediate 65-(4-Methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(4-Methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylase

Yield: 78%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.29 (d, J=9.0); 6.96 (d,J=9.0, 2H); 4.39 (q, J=7.2, 2H); 3.79 (br. t, J=5.0, 1H); 2.96 (br. s,1H); 2.19 (br. s, 1H); 2.08-1.96 (m, 2H); 1.96-1.74 (m, 8H); 1.39 (t,J=7.2, 3H).

Step 2:5-(4-Methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 95%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.28 (d, J=9.0, 2H); 6.98(d, J=9.0, 2H); 3.86 (s, 3H); 3.78 (t, J=5.4, 1H); 2.99 (br. s, 1H);2.21 (br. s, 2H); 2.10-1.70 (m, 10H).

Intermediate 75-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 63%. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 7.50-7.32 (m, 5H); 4.40 (q,J=7.5, 2H); 3.80 (t, J=5.4, 1H); 3.02 (br. t, J=4.8, 1H); 2.22 (br. s,2H); 2.07-1.95 (m, 2H); 1.95-1.76 (m, 8H); 1.40 (t, J=7.5, 3H).

Step 2;5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 91%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.58-7.42 (m, 3H); 7.37 (dd,J=7.8, 1.2, 2H); 3.80 (t, J=5.4, 1H); 3.06 (br. s, 1H); 2.22 (br. s,2H); 2.10-1.75 (m, 10H).

Intermediate 85(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 71%. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 7.52 (s, 1H); 7.34 (s, 2H);4.39 (q, J=6.9, 2H); 3.79 (br. t, J=5.4, 1H); 2.55 (br. t, J=4.6, 1H);2.19 (br. s, 2H); 2.10-1.60 (m, 10H); 1.39 (t, J=6.9, 3H).

Step 2:5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 95%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.57 (d, J=1.8, 1H); 7.38(dd, J=8.4, 1.8, 1H); 7.32 (d, J=8.4, 1H); 3.78 (br. t, J=5.4, 1H); 2.57(br, t, J=4.6, 1H); 2.20 (br. s, 2H); 2.10-2.65 (m, 10H).

Intermediate 95-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 56% ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.53-7.48 (m, 1H); 7.45-7.32(m, 3H); 4.40 (q, J=7.5, 2H); 3.80 (t, J=5.7, 1H); 2.57 (br. t, J=5.4,1H); 2.17 (m, 2H); 2.08-1.65 (m, 10H); 1.39 (t, J=7.5, 3H).

Step 2:5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 96%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.66 (br. s, 1H); 7.72(d, J=8.1, 1H); 7.70-7.51 (m, 3H); 3.68 (t, J=5.1, 1H); 2.46 (br. s,1H); 2.13 (br. s, 2H); 2.03-1.64 (m, 10H).

Intermediate 105-(5-chloropyridyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5-(5-chloropyridyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 28%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.46-8.44 (d, J=2.7, 1H);8.08 (dd, J=8.7, 2.7, 1H); 7.74 (d, J=8.7, 1H); 4.21 (q, J=6.9, 2H);3.13-3.06 (m, 2H); 2.12-1.62 (m, 12H); 1.12 (t, J=7.2, 3H).

Step 2:5-(5-chloropyridyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 78%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 13.25 (br. s, 1H), 8.44(d, J=2.5, 1H); 8.06 (dd, J=8.0, 2.5, 1H); 7.70 (d, J=8.1, 1H); 3.22(br. s, 1H); 3.05 (br. s, 1H); 2.12-1.64 (m, 12H).

Intermediate 115,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Step 1: Ethyl5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate

Yield: 97%. ¹H-NMR (δ ppm, CDCl₃): 4.36 (q, J=7.2, 2H); 3.61 (br. t,J=5.4, 1H); 3.10 (br. s, 1H), 2.16 (br. s, 2H); 2.08-1.95 (m, 4H);1.85-1.70 (m, 6H); 1.38 (t, J=7.2, 2H).

Step 2:5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid

Yield: 79%. ¹H-NMR (δ ppm, DMSO-d₆): 12.78 (br. s, 1H); 3.54 (br. s,1H); 2.97 (br. s, 1H); 2.09 (br. s, 2H); 1.97-1.85 (m, 4H); 1.77 (br. s,2H); 1.68 (t, J=12.0, 4H).

Intermediates 12a and Intermediate 12b Ethyl6-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate(intermediate 12a) and Ethyl5-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylate(Intermediate 12 b)

A solution of5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxylicacid (100 mg, 0.38 mmol) in DMF (2 ml) was treated with NaH (50%dispersion in mineral oil, 20 mg, 0.4 mmol) and stirred at roomtemperature for 45 minutes and then iodomethane (60 mg, 0.026 mmol) wasadded to the mixture. Stirring was continued for a further 1.5 h. Themixture was poured into water, extracted into ethyl acetate and driedover anhydrous sodium sulfate. Evaporation and separation by flashchromatography gave Intermediate 12a and Intermediate 12b.

Intermediate 12a: Yield: 36%. ¹H-NMR (δ ppm, CDCl₃): 4.37 (q, J=7.2,2H); 3.82 (s, 3H); 3.71 (t, J=5.4, 1H); 3.00 (br. t, J=4.8, 1H); 2.18(br. s, 2H); 2.10-1.80 (m, 4H); 1.80 (br. t, J=12.3, 6H); 1.39 (t,J=7.2, 3H). ¹³C-NMR (δ ppm, CDCl₃): 161.02, 158.50, 132.17, 127.49,60.58, 39.36, 36.29, 35.35, 34.69, 32.41, 28.63, 27.15, 14.2.1.

Intermediate 12b: Yield: 36%. ¹H-NMR (δ ppm, CDCl₃): 4.34 (q, J=7.2,2H); 4.02 (s, 3H); 3.54 (t, J=5.7, 1H); 3.03 (t, J=5.1, 1H); 2.14 (br.s, 2H); 2.07-1.93 (m, 4H); 1.84-1.67 (m, 6H); 1.37 (t, J=7.2, 3H).¹³C-NMR (δ ppm, CDCl₃): 163.32, 150.32, 136.54, 130.80, 60.32, 36.78,36.14, 34.65, 33.65, 29.57, 28.68, 26.46, 14.40.

Intermediates 13a and Intermediate 13b6-Pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4,7-diene-7-carboxylicacid (Intermediate 13a) and5-Pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxylicacid (Intermediate 13b)

Step 1: Ethyl6-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4,7-diene-7-carbaoxylate(Intermediate 13aa) and Ethyl5-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxylate(Intermediate 13bb)

Intermediate 13aa and 13bb were prepared by a procedure similar to thatdescribed for intermediate 12a and 12b, using intermediate 11 (1.00 g,3.84 mmol), DMF (3 ml) and 1-bromo-n-pentane ((53 μl, 4.20 mmol).

Intermediates 13aa: ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 4.39-4.28 (m, 4H);3.53 (t, J=5.4, 1H); 3.04 (t, J=5.4, 1H); 2.13 (br. s, 2H); 2.04-1.94(m, 4H); 1.84-1.66 (m, 8H); 1.37 (t, J=6.9, 3H); 1.30-1.24 (m, 4H); 0.88(t, J=6.9, 3H).

Intermediates 13bb: ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 4.37 (q, J=6.9, 2H);4.07 (t, J=7.5, 2H); 3.71 (br. s, 1H); 2.98 (br. s, 1H); 2.18 (br. s,2H); 2.02-1.92 (m, 4H); 1.85-1.71 (m, 8H); 1.38 (t, J=6.9, 3H);1.40-1.24 (m, 4H); 0.89 (t, J=7.2, 3H).

Step 2:6-Pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4,7-diene-7-carboxylicacid (Intermediate 13a) and5-Pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxylicacid (Intermediate 13b)

Intermediate 13aa (400 mg, 1.21 mmol) & Intermediate 13bb (400 mg, 1.21mmol), KOH (136 mg, 2.42 mmol), ethanol (10 ml) and H₂O (0.5 ml) yieldedintermediate 13a (270 mg, 73%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 4.39 (t,J=7.8, 2H); 3.64 (br. s, 1H); 3.07 (br. s, 1H); 2.14 (br. s, 2H);2.04-1.94 (m, 4H); 1.79-1.72 (m, 8H); 1.35-1.28 (m, 4H); 0.89 (t, J=7.5,3H) and intermediate 13b (290 mg, 79%). ¹H-NMR (δ ppm. CDCl₃, 300 MHz):4.06 (t, J=7.2, 2H); 3.70 (br. s, 1H); 2.98 (br. s, 1H); 2.18 (br. s,2H); 2.02-1.93 (m, 4H); 1.84-1.68 (m, 8H); 1.40-1.24 (m, 4H); 0.89 (t,J=7.2, 3H) respectively.

The intermediates 14 to 21 were prepared according to the process asdescribed in step 2 & step 3 of intermediate 1, using Ethyl2-oxo-2(3-oxobicyclo[2.2.1]hept-2-yl)acetate, appropriate(un)substituted phenyl hydrazine and alkali.

Intermediate 141-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylic acid

Step 1: Ethyl 2-oxo-2(3-oxobicyclo[2.2.1]hept-2-yl)acetate

The title product was prepared by a procedure similar to that describedin step 1 of intermediate 1, from hexamethyldisilazane (4.2 ml, 20.0mmol), ether (91 ml), nBuLi (2.3M in hexane, 11.63 ml, 27.3 mmol),norcamphor (2.0 g, 18.2 mmol) and diethyl oxalate (2.96 ml, 21.82 mmol)the title product was obtained.

Yield: 56%. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 11.41 (br. s, 1H); 4.35 (q,J=7.2, 2H); 3.81 (br. s, 1H); 2.81 (br. s, 1H); 2.05-1.85 (m, 3H); 1.80(br. d, J=10.5, 1H); 1.59 (br. t, J=7.2, 2H); 1.41 (t, J=7.2, 3H).

Step 2: Ethyl1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 52%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.73 (d, J=8.7, 2H); 7.47(t, J=7.2, 2H); 7.33 (t, J=7.2, 1H); 4.42 (q, J=7.2, 2H); 3.72 (br. s,1H); 3.68 (br. s, 1H); 2.13 (br. d, J=8.7, 1H); 2.05-1.95 (m, 2H); 1.72(d, J=8.7, 1H); 1.42 (t, J=7.2, 3H); 1.30-1.18 (m, 2H).

Step 3: 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 79%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.73 (d, J=7.8, 2H); 7.50(t, J=7.8, 2H); 7.36 (t, J=7.5, 1H); 3.75 (s, 1H); 3.72 (s, 1H); 2.17(br. d, J=9.0, 1H); 2.10-1.93 (m, 2H); 1.74 (d, J=8.7, 1H); 1.38-1.08(m, 2H).

Intermediate 151-(2-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 87%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.60 (m, 2H); 7.41-7.33(m, 2H); 4.42 (q, J=7.2, 2H); 3.69 (s, 1H); 3.40 (s, 1H); 2.14 (br. d,J=9.0, 1H); 2.05-1.82 (m, 2H); 1.72 (d, J=9.3, 1H); 1.30 (t, J=7.2, 3H);1.35-1.12 (m, 2H).

Step 2:1-(2-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 93%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.59-7.50 (m, 2H); 7.45-7.33(m, 2H); (dt, J=8.7, 1.8, 2H); 3.72 (s, 1H); 3.42 (s, 1H); 2.17 (br. d,J=8.7, 1H); 2.10-1.85 (m, 2H); 1.74 (d, J=8.7, 1H); 1.38-1.18 (m, 2H).

Intermediate 161-(4-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 72%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.60 (d, J=8.7, 2H); 7.43(d, J=8.7, 2H); 4.42 (q, J=7.2, 2H); 3.69 (br. s, 1H); 3.66 (br. s, 1H);2.14 (br. d, J=8.7, 1H); 2.10-1.95 (m, 2H); 1.72 (br. d, J=8.7, 1H);1.42 (t, J=7.2, 3H), 1.30-1.15 (m, 2H).

IR (KBr, cm⁻¹): 2977 (m), 2871 (m), 1716 (s), 1502 (s), 1373 (s), 1230(s), 1092 (s), 831 (m).

Step 2:1-(4-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 74.5%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (d, J=6.7, 2H); 7.50(d, J=6.7, 2H); 3.70 (s, 2H); 2.16 (br. d, J=8.7, 1H); 2.10-1.94 (m,2H); 1.74 (br. d, J=8.7, 1H); 1.2 (m, 2H). IR (KBr, cm⁻¹): 3460 (vs);2943 (m), 2873 (m), 1705 (vs), 1684 (vs), 1500 (vs), 1357 (s?), 1252(vs), 1093 (vs), 835 (s).

Intermediate 171-(2,4-Dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 51%. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 7.53 (d, J=2.4, 1H); 7.49 (d,J=8.4, 1H); 7.36 (dd, J=8.4, 2.4, 1H); 4.41 (q, J=7.2, 2H); 3.69 (br. s,1H); 3.38 (br. s, 1H); 2.14 (br. d, J=9.0, 1H); 2.07-1.82 (m, 2H); 1.70(br. d, J=9.0, 1H); 1.41 (t, J=7.2, 3H); 1.29-1.13 (m, 2H).

Step 2:1-(2,4-Dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 87%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d, J=2.1, 1H); 7.48(d, J=8.4, 1H); 7.38 (dd, J=8.4, 2.1, 1H); 3.71 (br. s, 1H); 3.41 (br s,1H); 2.16 (br. d, J=8.7, 1H); 2.07-1.82 (m, 2H); 1.72 (br. d, J=8.7,1H); 1.31-1.14 (m, 2H).

Intermediate 181-(2-Bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 79%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.69 (dd, J=7.8, 1.5, 1H);7.50 (dd, J=7.8, 2.1, 1H); 7.44 (td, J=7.8, 1.5, 1H); 7.32 (td, J=7.8,2.1, 1H); 4.41 (q, J=7.2, 2H); 3.69 (br. s, 1H); 3.39 (br. s, 1H); 2.18(br. d, J=9.0, 1H); 2.05-1.81 (m, 2H); 1.70 (d, J=8.7, 1H); 1.41 (t,J=7.2, 3H); 1.30-1.12 (m, 2H).

Step 2:1-(2-Bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 92%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.71 (dd, J=8.4, 1.5, 1H);7.53-7.40 (m, 2H); 7.34 (td, J=7.8, 2.1, 1H); 3.73 (br. s, 1H); 3.41(br. s, 1H); 2.19 (br. d, J=8.7, 1H); 2.04-1.82 (m, 2H); 1.73 (d, J=7.2,1.5, 1H); 1.32-1.15 (m, 2H).

Intermediate 191-(1-Bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 81%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.65-7.50 (m, 4H); 4.42 (q,J=7.2, 2H); 3.69 (s, 2H); 3.67 (s, 2H); 2.13 (br. d, J=8.7, 1H);2.06-1.95 (m, 2H); 1.74 (d, J=8.7, 1H); 1.42 (t, J=7.2, 3H); 1.28-1.15(m, 2H).

Step 2:1-(4-Bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 83%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.62 (s, 4H); 3.71 (s, 2H);2.17 (hr. d, J=9.0, 1H); 2.06-2.01 (m, 2H); 1.75 (d, J=9.0, 1H);1.30-1.17 (m, 2H).

Intermediate 201-(4-Fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 86%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.69 (dd, J=9.0, 4.8, 2H);7.15 (t, J=9.0, 2H); 4.42 (q, J=7.2, 2H); 3.67 (br. s, 2H); 3.40 (br. s,1H); 2.16 (br. d, J=8.7, 1H); 2.03-1.85 (m, 2H); 1.72 (br. d, J=9.0,1H); 1.43 (t, J=7.2, 3H); 1.32-1.17 (m, 2H).

Step 2:1-(4-Fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 60%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (dd, J=8.7, 4.8, 2H);7.18 (t, J=8.7, 2H); 3.70 (s, 2H); 2.17 (br. d, J=3.7, 1H); 2.10-1.90(m, 2H); 1.74 (d, J=8.7, 1H); 1.35-1.18 (m, 2H).

Intermediate 211-(2,4-Difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 81%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.80-7.68 (m, 1H); 7.05-6.95(m, 2H); 4.42 (q, J=7.2, 2H); 3.67 (br. s, 1H); 3.47 (br. s, 1H);2.12-2.08 (br. d, J=8.7, 1H); 2.03-1.90 (m, 2H); 1.72-1.65 (br. d,J=8.7, 1H); 1.41 (t, J=7.2, 3H); 1.30-1.17 (m, 2H).

Step 2:1-(2,4-Difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 78%. M.P.: 153-156° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.80-7.70(m, 1H); 7.10-6.97 (m, 2H); 3.70 (br. s, 1H); 3.50 (br. s, 1H); 2.12 (d,J=7.2, 1H); 2.08-1.86 (m, 2H); 1.72 (d, J=8.7, 1H); 1.35-1.17 (m, 2H).

Optical Resolution of1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid: Intermediate 21 Intermediate 21a

A slurry of intermediate 21 (racemic, 15.0 g, 51.72 mmol) inacetonitrile (LR grade) (150 ml) was treated with(S)-(−)-α-methylbenzylamine (3.66 ml, 28.44 mmol), stirred at RT for5-10 min and the mixture was heated at reflux for 15 min. Methanol (24ml) was added slowly till a clear solution resulted and heating wascontinued for further 30 min. after which the mixture was allowed tocool slowly to RT. The separated crystals were collected by filterationand washed with acetonitrile/MeOH 9:1 (˜15 ml). The acid was recoveredfrom the diastereomeric salt by dissolving in CH₂Cl₂ and extraction withaq. 1N HCl. Reiteration of the same procedure several times gave amixture (100 mg) enriched in the late eluting enantiomer [Intermediate21a, R_(t)=38.20 min. on a CHIRALCEL AS-H column (dimensions: 250×4.6mm, particle size: 5μ) using a 90:10:0.1 mixture ofn-hexane:isopropanol:trifluoroacetic acid as the eluent at 1 ml/min.flow rate]. M.P.: 114-115° C.; e.e=92%.

Intermediate 21b

The mother liquor obtained in the first step of the process describedabove was evaporated, distributed between CH₂Cl₂ and aq. 1N HCl and thelayers were separated. Drying (Na₂SO₄) and evaporation of the organiclayer gave a mixture of the two enantiomeric acids (9 g) enriched in thefast eluting enantiomer (R_(t)=34.65 min. under the same conditionsdescribed above; e.e=34%). The mixture was enriched in this enantiomerto an e.e of 91% (Intermediate 21b, yield=72 mg) by replacing(S)-(−)-α-methylbenzylamine with (R)-(+)-α-methylbenzylamine in theprocess described above for the late eluting enantiomer. M.P.: 110-112°C.

The intermediates 22 and 23 were prepared according to the process asdescribed in step 2 & step 3 of intermediate 1, using Ethyl2-(3-hydroxy-4,7,7-trimethyl bicyclo[2.2.1]hept-2-en-2-yl-2-oxoacetate,appropriate (un)substituted phenyl hydrazine and alkali.

Intermediate 221-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Step 1: Ethyl 2-(3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl-oxoacetate

A solution of DL-camphor (5 g, 33 mmol) in toluene (25 ml) was added toa slurry of sodium hydride (60% dispersion, 1.34 g, 56 mmol) and diethyloxalate (6.69 g, 49 mmol) in toluene (30 ml) at 60″C and the mixturestirred at the same temperature for 1 hour. The reaction mixture wasquenched into ice, acidified with 1N HCl, extracted with ethyl acetateand the organic layers dried over Na₂SO₄ and the solvent was removedunder vacuum to give the title product (7.3 g, 88%) which was usedwithout further purification for the next step.

Yield: 88%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 11.39 (br. s, 1H); 4.35 (q,J=7.2, 2H); 3.29 (d, J=4.2, 1H); 2.30-2.04 (m, 1H); 1.70-1.40 (m, 1H);1.46 (hr. d, J=8.7, 2H); 1.38 (t, J=7.2, 3H); 1.01, 0.97, 0.83 (3s, 9H).

Step 2: Ethyl1-(2,4-dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 42%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.53 (s, 1H); 7.36 (s, 2H);4.40 (q, J=7.2, 2H); 3.16 (d, J=3.6, 1H); 2.13 (m, 1H); 1.40 (t, J=7.2,3H); 1.26 (m, 2H); 0.88 (s, 6H); 0.83 (s, 3H).

Step 3:1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Yield: 72%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.80 (br. s, 1H); 7.95(d, J=2.1, 1H); 7.67 (d, J=8.7, 1H); 7.63 (dd, J=8.7, 2.1, 1H); 3.01 (d,J=3.6, 1H); 2.13-2.06 (m, 1H); 1.79 (br. t, J=8.7, 1H); 1.32 (hr. t,J=9.3, 1H); 1.16-1.00 (m, 1H); 0.88 (s, 3H); 0.84 (s, 3H); 0.77 (s, 3H).

Intermediate 233-(2,4-difluorophenyl)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Step 1: Ethyl3-(2,4-difluorophenyl)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylate

Yield: 42%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.58-7.48 (m, 1H); 7.03-6.80(m, 2H); 4.40 (q, J=7.2, 2H); 3.15 (d, J=4.2, 1H); 2.20-2.08 (m, 1H);1.88-1.76 (m, 1H); 1.40 (t, J=7.2, 3H); 1.40-1.08 (m, 2H); 0.99, 0.92,0.79 (3s, 9H).

Step 2:3-(2,4-difluorophenyl)-1,10,10-trimethyl-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Yield: 72%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.80 (br. s, 1H);7.80-7.57 (m, 2H); 7.29 (br. t, J=8.4, 1H); 3.0.1 (d, J=3.6, 1H);2.08-2.02 (m, 1H); 1.79 (br. t, J=9.6, 1H); 1.32 (br. t, J=9.0, 1H);1.06 (br. t, J=9.0, 1H); 0.91, 0.88, 0.73 (3s, 9H).

The intermediate 24 and 25 were prepared according to the process asdescribed in step 2& step 3 of intermediate 1, using Ethyl2-oxo-2-(10-oxotricyclo[6.2.2.0^(2,7)]dodeca-2,4,6-trien-9-yl)acetate,appropriate (un)substituted phenyl hydrazine and alkali.

Intermediate 2410-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

Step 1: Ethyl2-oxo-2-(10-oxotricyclo[6.2.2.0^(2,7)]dodeca-2,4,6-trien-9-yl)acetate

The title product was prepared by a procedure similar to that describedfor step 1 of intermediate 1. Fromtricyclo[6.2.2.0^(2,7)]dodeca-2,4,6-trien-9-one [prepared by one of themethods available in the art of organic synthesis, e.g., as described inHales et. al. Tetrahedron, 1995, 51, 7777-7790] (2.5 g, 14.53 mmol),hexamethyldisilazane (4.9 ml, 23.2 mmol), 2.34M n-BuLi (10 ml, 23.4mmol) and diethyl oxalate (3.18 ml, 21.18 mmol) the desired product wasobtained (2.3 g, 63%).

Yield: 63%. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 12.9 (s, 1H); 7.20-7.15 (m,4H); 4.91 (s, 1H); 4.31 (q, J=7.2, 2H); 3.79 (s, 1H); 2.00-1.90 (m, 2H);1.73-1.60 (m, 2H); 1.34 (t, J=7.2, 3H).

Step 2: Ethyl10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]-pentadeca-2,9,6,9(13),11-pentaene-12-carboxylate

Yield: 91%. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.58 (d, J=2.2, 1H); 7.45(d, J=8.5, 1H); 7.38 (dd, J=8.5, 2.0, 1H); 7.33 (br. d, J=7.0, 1H); 7.16(br. d, J=7.08, 1H); 7.13 (td, J=7.6, 1.5, 1H); 7.08 (td, J=7.5, 1.5,1H); 4.91 (s, 1H); 4.45 (q, J=7.2, 2H); 4.29 (s, 1H); 1.81-1.72 (m, 4H);1.43 (t, J=7.2, 3H).

Step 3:10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

¹H-NMR (δ ppm, CDCl₃, 400 MHz): 7.60 (d, J=2.1, 1H); 7.45 (d, J=8.5,1H); 7.41 (dd, J=8.5, 2.1, 1H); 7.35 (br. d. J=6.8, 1H); 7.17 (br. d,J=7.2, 1H); 7.14 (td, J=7.5, 1.3, 1H); 7.09 (td, J=7.5, 1.3, 1H); 4.94(s, 1H); 4.32 (s, 1H); 1.82-1.73 (m, 4H).

Intermediate 2510-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

Step 1: Ethyl10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxylate

Yield: 71%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.67-7.57 (m, 1H); 7.34 (d,J=6.9, 1H); 7.20-7.01 (m, 5H); 4.90 (s, 1H); 4.44 (q, J=6.9, 2H); 4.39(br. s, 1H); 1.79 (s, 4H); 1.45 (t, J=6.9, 3H).

Step 2:10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

Yield: 86%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.68-7.58 (m, 1H); 7.35 (d,J=7.2, 1H); 7.2.1-7.04 (m, 5H); 4.94 (s, 1H); 4.41 (br. s, 1H); 1.81(br. s, 41-1)

The intermediate 26 was prepared according to the process as describedin step 2 & step 3 of intermediate 1, using Ethyl9endo,13endo-2-[11-(4-chlorophenyl)-10,12,15-trioxo-11-azatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6-trien-14-yl]-2-oxoacetateappropriate (un)substituted phenyl hydrazine and alkali.

Intermediate 2613Endo,14endo-16-(4-chlorophenyl)-15,17-dioxo-10-(2,4-dichlorophenyl)-10,11,16-triazapentacyclo[6.5.5.0^(2,7).0^(9,13). 0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxylic acid

Step 1:9-Endo,13-endo-11-(4-chlorophenyl)-11-azatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6-triene-10,12,14-trione

A solution of11-oxatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6-triene-10,12,14-trione[prepared as described by Takeda et. al. Tetrahedron 1970, 26,1435-1451] (1.0 g, 4.11 mmols), 4-chloroaniline (1.2 g, 9.05 mmols) inxylene was refluxed for 6 h. Water was added to the reaction mixture andextracted with AcOEt. Organic layers dried over Na₂SO₄ and the solventevaporated. The residue, after PC (AcOEt-petroleum ether 4:96→16:84)gave the title product (930 mg, 65%).

Yield: 65%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.40-7.222 (m, 6H); 6.47 (d,J=8.7, 2H); 4.18 (dd, J=3.3, 1H); 4.07-4.02 (m, 1H); 3.59 (dd, J=8.7,3.3, 1H); 3.49 (dd, J=8.4, 3.3, 1H); 2.56 (dd, J=20.4, 2.1, 1H); 2.43(dd, J=20.4, 3.3, 1H).

Step 2: Ethyl9endo,13endo-2-[11-(4-chlorophenyl)-10,12,15-trioxo-11-azatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6-trien-14-yl]-2-oxoacetate

The title product was prepared by a procedure similar to that describedfor step 1 of intermediate 1. From9-Endo,13-endo-11-(4-chlorophenyl)-11-azatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6-triene-10,12,14-trione(800 mg, 2.28 mmol), hexamethyldisilazane (0.68 ml, 3.2 mmol), n-BuLi(15% in hexane, 1.31 ml, 3.1 mmol) and diethyl oxalate (0.62 ml, 4.6mmol) title product (530 mg, 52%) was obtained in pure form after FC.

Yield: 52%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 13.0 (br. s, 1H); 7.36-7.20(m, 6H); 6.47 (d, J=7.2, 2H); 5.54 (br. s, 1H); 4.49-4.38 (m, 3H); 3.54(br. s, 2H); 1.45 (t, J=7.2, 3H).

Step 3: Ethyl13endo,14endo-16-(4-chlorophenyl)-15,17-dioxo-10-(2,4-dichlorophenyl)-10,11,16-triazapentacyclo[6.5.5.0^(2,7).0^(9,13).0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxylate

Yield: 66%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63 (d, J=2.4, 1H); 7.51(d, J=8.4, 1H); 7.47-7.35 (m, 3H); 7.30-7.15 (m, 4H); 6.44 (d, J=9.0,2H); 5.44 (d, J=3.0, 1H); 4.83 (d, J=2.7, 1H); 4.49 (q, J=7.2, 2H); 3.56(dd, J=8.7, 3.3, 1H); 3.48 (br. d, 8.7, 1H); 1.46 (t, J=7.2, 3H).

Step 4:13Endo,14endo-16-(4-chlorophenyl)-15,17-dioxo-10-(2,4-dichlorophenyl)-10,11,16-triazapentacyclo[6.5.5.0^(2,7).0^(9,13).0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

Yield: 76%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66 (d, J=2.4, 1H);7.54-7.40 (m, 3H); 7.28-7.19 (m, 5H); 6.45 (d, J=8.7, 2H); 5.50 (d,J=3.0, 1H); 4.87 (d, T=3.0, 1H); 3.59 (dd, J=8.7, 3.0, 1H); 3.50 (br. d,J=8.7, 1H).

Intermediate 2710-(2,4-Difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

Step 1: Ethyl2-oxo-2-(10-oxotricyclo[6.2.1.0^(2,7)]undeca-2(7),3,5-trien-9-yl)acetate

The title product was prepared by a procedure similar to that describedfor step 1 of intermediate 22. From Benzonorbornanone (2.4 g, 15.1.8mmol), sodium hydride (60% dispersion, 619 mg, 25 mmol) and diethyloxalate (3.09 ml, 22.7 mmol) title product (2.6 g, 52%) was obtained.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 10.63 (br. s, 1H); 7.75-7.20 (m, 5H);4.81 (d, J=1.5, 1H); 4.35 (q, J=7.2, 2H); 3.75 (d, J=1.5, 1H); 2.57 (dt,J=9.3, 1.8, 1H); 2.42 (d, J=8.7, 1.5, 1H); 1.43 (t, J=7.2, 3H).

Step 2: Ethyl10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxylate

The title product was prepared by a procedure similar to that describedfor step 3 of intermediate 20. From Ethyl(2Z)-hydroxy(10-oxotricyclo[6.2.1.0^(2,7)]undeca-2,4,6-trien-9-ylidene)acetate(1.0 g, 3.87 mmol), 2,4-difluorophenylhydrazine hydrochloride (838 mg,4.64 mmol) ethanol (13.0 ml) and acetic acid (15.0 ml) title product(1.21 g, 85%) was obtained. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.79-7.69(m, 1H); 7.35-7.26 (m, 2H); 7.05-6.94 (m, 4H), 4.52 (br. s, 1H), 4.41(q, J=7.5, 2H); 4.32 (br. s, 1H); 3.00 (br. d, J=8.1, 1H); 2.85 (dt,J=8.1, 1.5, 1H); 1.41 (t, J=7.5, 3H).

Step 3:10-(2,4-Difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxylicacid

The title product was prepared by a procedure similar to that describedfor intermediate. From Ethyl10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxylateKOH (367 mg, 6.5 mmol), ethanol (10.4 ml) and H₂O (0.5 ml) title product(810 mg, 73%) was obtained. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.95 (m,1H); 7.78-7.57 (m, 2H); 7.32-7.25 (m, 3H); 6.98-6.89 (m, 2H); 4.43 (s,2H); 2.89 (d, J=8.1, 1H); 2.71 (d, J=8.1, 1H).

The intermediate 28 to 30 were prepared according to the process asdescribed in step 2 & step 3 of intermediate 1, using Ethyl2-hydroxy-2-(3-oxabicyclo[2.2.2]octa-2-yliden)acetate appropriate(un)substituted phenyl hydrazine and alkali.

Intermediate 283-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.2.0^(2,6)]undeca-2(6),4-diene-5-carboxylicacid

Step 1: Ethyl 2-hydroxy-2-(3-oxabicyclo[2.2.2]octa-2-yliden)acetate

A solution of bicyclo[2.2.2]octan-2-one (2.4 g, 19.35 mmol) in toluene(20 ml) was added to a slurry of sodium hydride (60% dispersion, 603 mg,25.16 mmol) and diethyl oxalate (3.15 ml, 23.22 mmol) in toluene (10mmol) at 60° C. and the mixture stirred at the same temperature for 1hour. The reaction mixture was quenched into ice, acidified with 1N HCl,extracted with ethyl acetate and the organic layers dried over Na₂SO₄and the solvent was removed under vacuum to give Intermediate 28 (1.2 g,27%) which was used without further purification for the next step.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 13.80 (br. s, 1H); 4.36 (q, J=6.9, 2H);3.57 (br. s, 1H); 2.52 (br. s, 1H); 1.82-1.60 (m, 8H); 1.38 (t, J=6.9,3H).

Step 2:Ethyl-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.2.0^(2,6)]undeca-2(6),4-diene-5-carboxylate

Yield: 48%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70-7.60 (m, 1H); 7.06-6.94(m, 2H); 4.43 (q, J=7.2, 2H); 3.70 (br. s, 1H); 3.15 (br. s, 1H); 1.78(d, 7.8, 4H); 1.45-1.36 (m, 7H).

Step 3:3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.2.0^(2,6)]undeca-2(6),4-diene-5-carboxylicacid

Yield: 90%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.72-7.60 (m, 1H); 7.09-6.98 (m, 2H); 3.73 (br. s, 1H); 3.18 (br.s, 1H); 1.80 (d, J=6.6, 4H); 1.40 (d, J=7.8, 4H).

Intermediate 293-(3,4-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Step 1: Ethyl3-(3,4-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylate

Yield: 69%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.90 (d, J=2.1, 1H); 7.59(dd, J=7.5, 2.1, 1H); 7.52 (d, J=8.7, 1H); 4.42 (q, J=7.5, 2H); 3.71(br. s, 1H); 3.66 (br. s, 1H); 2.14 (d, J=8.7, 1H); 2.00 (d, J=8.4, 2H);1.73 (d, J=9.3, 1H); 1.42 (t, J=7.5, 3H); 1.20 (d, J=6.9, 2H).

Step 2:3-(3,4-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Yield: 90%. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.92-7.87 (m, 1H); 7.62-7.52(m, 2H); 3.73 (br. s, 1H); 3.71 (br. s, 1H); 2.16 (d, J=6.6, 1H); 2.03(d, J=6.3, 2H); 1.76 (d, J=8.7, 1H); 1.23 (d, J=6.0, 2H).

Intermediate 303-(2-ethoxy-4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Step 1: Ethyl3-(2-ethoxy-4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylate

¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.53 (q, J=6.3, 1H); 6.78-6.66 (m, 2H);4.40 (q, J=6.9, 2H); 4.10-4.00 (m, 2H); 3.65 (br. s, 1H); 3.35 (br. s,1H); 2.08 (d, J=8.1, 1H); 2.00-1.80 (m, 2H); 1.66 (d, J=9.0, 1H);1.44-1.32 (m, 6H); 1.24 (d, J=6.0, 2H).

Step 2:3-(2-ethoxy-9-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Yield: 0.91%. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.62 (br. s, 1H); 7.48(t, J=7.8, 1H); 7.18 (d, J=8.4, 1H); 6.94-6.86 (m, 1H); 4.17 (d, J=6.6,2H); 3.49 (br. s, 1H); 3.34 (br. s, 1H); 2.00-1.88 (m, 3H); 1.63 (d,J=7.8, 1H); 1.30 (t, J=6.6, 1H); 1.09 (t, J=10.5. 2H).

The intermediates 31a & 31b, 32a & 32b were prepared according to theprocess as described for intermediate 12a & 12 b followed by hydrolysisas described for intermediate 13a & 13b, using Ethyl2-oxo-2(3-oxobicyclo[2.2.1]hept-2-yl)acetate hydrazine hydrate, 4-methylbenzyl bromide and 4-fluoro benzyl bromide respectively.

Intermediate 31a

Step 1: Ethyl 4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate

Yield: 1.30 g, 66%. ¹H-NMR (δ ppm, CDCl₃): 4.36 (q, J=6.9, 2H); 3.58(br. s, 1H); 3.45 (br. s, 1H), 2.02-1.92 (m, 3H); 1.71 (d, J=9.0, 1H);1.38 (t, J=6.9, 3H); 1.30-1.20 (m, 2H).

Step 2: Ethyl1-(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate:(Intermediate 31aa) and

Ethyl2-(4-methylbenzyl)-4,5,6,7-tetrahydro-2H-4,7-methano-indazole-3-carboxylate(Intermediate 31 bb)

Intermediate 31aa; ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.15 (s, 4H); 5.28(d, J=4.8, 2H); 4.38 (q, 7.2, 2H); 3.54 (br. s, 1H); 2.97 (br. s, 1H);2.34 (s, 3H); 1.98-1.78 (m, 3H); 1.52 (d, J=8.7, 1H); 1.39 (t, J=6.9,3H); 1.12-0.98 (m, 1H); 0.82-0.68 (m, 1H).

Intermediate 31bb: ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.20-7.05 (m, 4H);5.72 (d, J=15.6, 1H); 5.49 (d, 14.7, 1H); 4.38-4.25 (m, 2H); 3.52 (br.s, 1H); 3.41 (br. s, 1H); 2.29 (s, 3H); 2.22 (br. s, 1H); 1.99-1.80 (m,2H); 1.66 (d, J=7.2, 1H); 1.35 (t, J=6.9, 3H); 1.26-1.19 (m, 2H)

Step 3a:3-(4-methylbenzyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxylicacid

Intermediate 31a (294 mg, 82%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.15 (s,4H); 5.27 (d, J=3.6, 2H); 3.57 (br. s, 1H); 3.03 (br. s, 1H); 2.34 (s,3H); 1.96-1.81 (m, 2H); 1.74-1.65 (m, 1H); 1.55 (d, J=9.0, 1H);1.12-1.02 (m, 1H); 0.83-0.74 (m, 1H).

Step 3b:2-(4-Methylbenzyl)-4,5,6,7-tetrahydro-2H-4,7-methano-indazole-3-carboxylicAcid

Intermediate 31b: (68 mg, 85%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.10 (d,J=3.3, 4H); 5.72 (d, 15.0, 1H); 5.49 (d, J=14.4, 1H); 3.58 (br. s, 1H);3.42 (br. s, 1H); 2.29 (s, 3H); 1.99-1.88 (m, 3H); 1.67 (d, J=8.7, 1H);1.23 (d, J=10.5, 2H).

Intermediate 32a and 32b

Step 1: Ethyl1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylate(Intermediate 32aa) and

Ethyl2-(1-fluorobenzyl)-4,5,6,7-tetrahydro-2H-4,7-methano-indazole-3-carboxylate(Intermediate 32bb)

Intermediates 32aa: ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.28-7.20 (m, 2H);7.03 (t, J=8.7, 2H); 5.29 (d, J=3.3, 2H); 4.38 (q, 6.9, 2H); 3.55 (br.s, 1H); 3.02 (br. s, 1H); 1.98-1.79 (m, 2H); 1.70-1.62 (m, 1H); 1.55 (d,J=9.0, 1H); 1.39 (t, j=6.9, 3H); 1.14-0.98 (m, 1H); 0.82-0.68 (m, 1H).

Intermediates 32bb: ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.24-7.17 (m, 2H);6.95 (t, J=8.4, 2H); 5.72 (d, J=15.6, 1H); 5.48 (d, 15.0, 1H); 4.29 (q,J=7.2, 2H); 3.51 (br. s, 1H); 3.40 (br. s, 1H); 1.94 (d, J=6.0, 3H);1.66 (d, J=9.0, 1H); 1.35 (t, J=7.2, 3H),1.28-1.18 (m, 2H).

Step 2a:1-(4-Fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxylicacid

Intermediate 32a: (294 mg, 72%). ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 12.42(br. s, 1H); 7.36-7.25 (m, 2H); 7.20 (t, J=9.0, 2H); 5.31 (br. s, 2H);3.39 (br. s, 1H); 3.32 (br. s, 1H); 1.90-1.70 (m, 3H); 1.55 (d, J=8.7,1H); 0.99-0.80 (m, 1H); 0.79-0.62 (m, 1H).

Step 2b:2-(4-Fluorobenzyl)-4,5,6,7-tetrahydro-2H-4,7-methano-indazole-3-carboxylicacid

Intermediate 32b: (55 mg, 60%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.25-7.17 (m, 2H); 6.96 (t, J=8.7, 2H); 5.72 (d, J=14.4, 1H); 5.50 (d,15.3, 1H); 3.59 (br. s, 1H); 3.43 (br. s, 1H); 1.84 (d, J=6.9, 3H); 1.69(d, J=8.4, 1H); 1.23 (d, J=10.2, 2H).

Example 101N(7)-Piperidino-5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-arboxamide

A solution of intermediate 1 (300 mg, 0.78 mmol) in DMF (3 ml), wastreated with BOP reagent (319 mg, 0.72 mmol) and Et₃N (0.10 ml, 0.99mmol) at room temperature for 15 minutes after which period,N-aminopiperidine (80 μl, 0.90 mmol) was added to the mixture andstirred at room temperature for 1 h. The mixture was poured into waterand the precipitate formed was collected, by filtration, dried andpurified by flash chromatography to get pure title compound (270 mg,74%). M.P.: 244° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72 (d, J=7.6, 1H);7.65 (br. s, 1H); 7.50-7.30 (m, 3H, 3.97 (br. s, 1H); 2.85 (br. s, 4H);2.51 (br. s, 1H); 2.16 (br. s, 2H); 2.10-1.50 (m, 14H); 1.40 (br. s,2H). IR (cm⁻¹, KBr): 3311 (w), 2913 (s), 2844 (m), 2793 (m), 1687 (s),1570 (w), 1522 (s), 1489 (m), 1479 (m), 1440 (m), 1352 (m), 1227 (m),1214 (m). MS (m/z) 469.4 ([M+H]⁺).

Example 102N(7)-Benzyl-5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101 Intermediate 1 (300 mg, 0.78 mmol), DMF (3ml), Et₃N (0.10 ml, 0.99 mmol), BOP reagent (319 mg, 0.72 mmol) andbenzylamine (80 μl, 0.72 mmol) gave the title compound (280 mg, 76%).M.P.: 201° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (d, J=7.5, 1H); 7.44(dd, J=7.5, 1.5, 1H); 7.41-7.20 (m, 8H); 4.63 (dd, J=14.4, 6.0, 1H);4.50 (dd, J=16.5, 5.4, 1H); 4.00 (br. t, J=5.1, 1H); 2.52 (hr. t, J=5.1,1H); 2.13 (br. s, 2H); 2.13-1.92 (m, 4H); 1.92-1.65 (m, 6H). IR (cm⁻¹,KBr): 3428 (m), 2908 (s), 2845 (m), 1672 (s), 1.566 (m), 1522 (s), 1498(s), 1472 (s), 1351 (m), 1087 (m), 1024 (m), 1010 (m), 778 (m), 763 (m),726 (m), 698 (m). MS (m/z): 476.4 ([M+H]⁺).

Example 103N(7)-Morpholino-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) andN-aminomorpholine (28 μl, 0.29 mmol) yielded the title compound (97 mg,78%). M.P.: 220° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.75 (br. s, 1H);7.47 (d, J=8.1, 2H); 7.29 (d, J=8.1, 2H); 3.96 (br. s, 1H); 3.85 (t,J=4.5, 4H); 2.99 (br. s, 1H); 2.95 (t, J=4.5, 5H); 2.20 (br. s, 2H);2.10-1.76 (m, 10H). IR (KBr, cm⁻¹): 2915 (s), 2848 (m), 1674 (s), 1532(m), 1498 (s), 1304 (m), 1267 (m), 1219 (m), 1112 (s), 1091 (s), 895(m), 838 (s). MS (m/z): 427.3 ([M+H]⁺).

Example 104N(7)-(3-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (128 mg, 0.29 mmol) and3-aminomethylpyridine (30 μl, 0.29 mmol) furnished the title compound(98 mg, 78%). M.P.: 180° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.76 (t,J=6.0, 1H); 8.52 (br. s, 1H); 8.43 (dd, J=4.8, 1.5, 1H); 7.70 (d, J=8.1,1H); 7.62 (d, J=8.4, 2H); 7.46 (d, J=8.4, 2H); 7.34 (dd, J=8.1, 4.8,1H); 4.39 (d, J=6.0, 2H); 3.80 (br. s, 1H); 2.95 (br. s, 1H); 2.14 (br.s, 2H), 2.00-1.69 (m, 10H). MS (m/z): 433.2 ([M+H]⁺).

Example 105N(7)-(4-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (0.128 mg, 0.29 mmol) and4-aminomethylpyridine ((30 μl, 0.29 mmol) furnished the title compound(119 mg, 94%). M.P.: 167-168° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.79(t, J=6.3, 1H); 8.48 (d, J=4.5, 2H); 7.65 (dd, J=7.5, 1.5, 2H); 7.48(dd, J=7.5, 1.5, 2H); 7.27 (d, J=4.5, 2H); 4.39 (d, J=5.7, 2H); 3.80(br. s, 1H); 2.97 (br. s, 1H); 2.14 (br. s, 2H), 2.00-1.68 (m, 10H). IR(cm⁻¹, KBr): 3212 (m), 2913 (s), 2850 (m), 1656 (s), 1529 (m), 1498 (s),1419 (m), 1363 (m), 1232 (m), 1160 (m), 1084 (m), 842 (m). MS (m/z):433.1 ([M+H]⁺).

Example 106N(7)-Cyclohexyl-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,1).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) andcyclohexylamine (40 μl, 0.29 mmol) gave the title compound (110 mg,89%). M.P.: 162° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.47 (d, J=8.7, 2H);730 (d, J=8.7, 2H); 6.85 (d, J=8.7, 1H); 4.01 (br. t, J=5.5, 1H);4.00-3.80 (m, 1H); 2.99 (br. t, J=5.6, 1H); 2.20 (br. s, 2H); 2.08-1.68(m, 12H); 1.48-1.10 (m, 8H). IR (cm⁻¹, KBr): 3336 (m), 2928 (s), 2909(s), 2846 (m), 1649 (s), 1537 (s), 1498 (s), 1366 (m), 1231 (m), 1164(m), 1088 (m), 838 (m). MS (m/z): 424.1 ([M+H]⁺).

Example 107N(7)-(N-cyclohexyl-N-methylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3ml), Et₃N (0.22.0 ml, 1.60 mmol), BOP reagent (322 mg, 0.72 mmol) and3-N-cyclohexyl-N-methyl hydrazine (140 mg, 1.10 mmol) yielded the titlecompound (215 mg, 65%). M.P.: 219° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.64 (br. s, 1H); 7.46 (d, J=9.0, 2H), 7.31 (d, J=9.0, 2.1, 2H), 3.97(br. s, 1H); 2.98 (br. s, 1H), 2.69 (s, 3H), 2.62 (br. s, 1H); 2.19 (br.s, 2H); 2.05-1.70 (m, 14H); 1.40-1.00 (m, 6H). IR (cm⁻¹, KBr): MS (m/z):453.20 ([M+H]⁺).

Example 108N(7)-Cyclohexylmethyl-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et₃N (40μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) andcyclohexanemethylamine (38 μl, 0.23 mmol) gave the title compound (93mg, 73%). M.P.: 117° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.46 (d, J=8.1,2H); 7.29 (d, J=8.1, 2H); 7.03 (br. s, 1H); 4.01 (br. s, 1H), 3.22 (t,J=6.6, 2H); 3.00 (br. s, 1H); 2.20 (br. s, 2H); 2.10-1.50 (m, 15H);1.40-1.10 (m, 4H), 1.10-0.85 (m, 2H). IR (cm⁻¹, KBr): 3441 (m), 2924(s), 2849 (m), 1670 (s), 1528 (m), 1499 (s), 1477 (m), 1364 (m), 1214(m), 1232 (m), 1162 (w), 1087 (m), 838 (m). MS (m/z): 438.2 ([M+H]⁺).

Example 109N(7)-(Adamantan-1-yl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (154 mg, 0.35 mmol) and1-adamantylamine (52 mg, 0.35 mmol) furnished the title compound (117mg, 70%). M.P.: 249-252° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.47 (d,J=8.7, 2H); 7.29 (d, J=8.7, 2H); 6.73 (br. s, 1H); 4.00 (br. s, 1H);2.98 (br. s, 1H); 2.23-1.54 (m, 27H). IR (cm⁻¹, KBr): 3389 (s), 2904(s), 2849 (m), 1674 (s), 1561 (w), 1527 (s), 1499 (s), 1479 (m), 1455(m), 1364 (m), 1356 (m), 1232 (m), 1219 (m), 1170 (w), 1090 (m), 1014(w), 837 (m). MS (m/z): 476.2 ([M+H]⁺).

Example 110N(7)-(1S,2endo-1,3,3-Trimethyl-bicyclo[2.2.1]hept-2-yl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (154 mg, 0.35 mmol) and1,3,3-Trimethyl-bicyclo[2.2.1]hept-2-yl amine (53 mg, 0.80 mmol)furnished the title compound (135 mg, 80%). M.P.: 229° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.91 (s, 1H); 7.47 (d, J=8.7, 2H); 7.39 (d, J=8.1, 2H);7.34-7.20 (m, 3H); 6.99 (t, J=8.8, 1H); 3.86 (br. t, J=4.8, 1H); 3.35(s, 3H); 3.00 (br. s, 1H); 2.17 (br. s, 2H); 2.00-1.70 (m, 10H). IR(cm⁻¹, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m),1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m),1092 (s), 1083 (m), 1014 (m), 837 (s). MS (m/z): 478.3 ([M+H]⁺).

Example 111N(7)-(2-Chlorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and2-chlorobenzylamine (35 μl, 0.29 mmol) yielded the title compound (102mg, 75%). M.P.: 162-164° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.18(m, 9H); 4.67 (d, J=6.3, 2H); 3.99 (br. t, J=4.3, 1H); 3.00 (br. t,J=4.8, 1H); 2.20 (br. s, 2H); 2.00-1.70 (m, 10H). IR (KBr, cm⁻¹): 3422(m), 2916 (s), 2845 (m), 1670 (s), 1564 (m), 1531 (s), 1497 (s), 1478(s), 1442 (m), 1360 (m), 1249 (m), 1232 (m), 1163 (m), 1085 (s), 1047(m), 1012 (m), 976 (m), 835 (m). MS (m/z): 466.0 ([M+H]⁺).

Example 112N(7)-(4-Chlorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et₃N (40μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and 4-chlorobenzylamine(36 μl, 0.29 mmol) gave the title compound (115 mg, 85%). M.P.: 198° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.45 (d, J=8.7, 2H); 7.40-7.20 (m, 7H);4.54 (d, J=6.3, 2H), 4.00 (br. s, 1H); 3.00 (br. s, IR); 2.21 (br. s,2H); 2.10-1.95 (m, 2H); 1.95-1.70 (m, 8H). IR (cm⁻¹, KBr): 331.7 (m),2914 (s), 2847 (m), 1657 (s), 1538 (s), 1498 (s), 1365 (m), 1247 (m),1087 (m), 1015 (m); 839 (m). MS (m/z): 466.3 ([M+H]⁺).

Example 113N(7)-(4-Fluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and4-fluorobenzylamine (33 μl, 29 mmol) gave the title compound (96 mg,73%). M.P.: 201° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.44 (d, J=8.4, 2H);7.30-7.25 (m, 5H); 7.00 (t, J=8.4, 2H); 4.54 (d, J=6.0, 2H), 4.01 (br.s, 1H); 3.00 (br. s, 1H); 2.20 (br. s, 2H); 2.05-1.95 (m, 2H); 1.95-1.80(m, 8H). IR (cm⁻¹, KBr): 3345 (m), 2921 (s), 2900 (m), 2850 (m), 1648(s), 1542 (s), 1508 (s), 1364 (m), 1354(m), 1258 (m), 1233 (m), 1217(s), 1155 (m), 1087 (m), 834 (s). MS (m/z): 450.0 ([M+H]⁺).

Example 114N(7)-(2,4-Difluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example, 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0ml), Et₃N (60 μl, 0.43 mmol), BOP reagent (193 mg, 0.43 mmol) and2,4-difluorobenzylamine (52 μl, 0.43 mmol) yielded the title compound(195 mg, 96%). M.P.: 185° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.49-7.27(m, 6H); 6.90-6.75 (m, 2H); 4.57 (d, J=6.3, 2H), 3.98 (t, J=5.7, 1H);2.99 (br. t, 5.4, 1H), 2.20 (br. s, 2H), 2.05-1.80 (m, 10H). IR (cm⁻¹,KBr): 3428 (s), 2920 (m), 2898 (m), 1673 (s), 1535 (s), 1500 (s), 1430(s), 1229 (m), 1161 (m), 1064 (m), 986 (m), 835(m), 960 (m), 861 (m). MS(In/z): 468.10 ([M+H]⁺).

Example 115N(7)-(2,6-Difluorobenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0ml), Et₃N (60 μl, 0.43 mmol), BOP reagent (193 mg, 0.43 mmol) and2,6-difluorobenzylamine (52 μl, 0.43 mmol) yielded the title compound(178 mg, 87%). M.P.: 166-167° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.44(d, J=8.7, 2H); 7.30-7.20 (m, 3H); 6.88 (t, J=7.8, 2H), 4.68 (d, J=5.7,2H), 4.00 (br. t, J=5.4, 1H); 2.98 (br. s, 1H), 2.19 (br. s, 2H),2.05-1.60 (m, 10H). IR (cm⁻¹, KBr): 3427 (m), 2930 (m), 2905 (m), 1681(s), 1594 (m), 1563 (m), 1530 (s), 1499 (s), 1471 (s), 1364 (m), 1260(m), 1161 (m), 1087 (s), 994 (s), 839 (m). MS (m/z): 468.10([M+H]^(+s)).

Example 116N(7)-(4-Trifluoromethylbenzyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et₃N (40μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and4-(trifluoromethyl)benzylamine (42 μl, 0.27 mmol) furnished the titlecompound (115 mg, 79%). M.P.: 228° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.57 (d, J=8.6, 2H); 7.46-7.39 (m, 4H); 7.37 (hr. t, J=5.4, 1H); 7.28(d, J=8.7, 2H); 4.63 (d, J=6.0, 2H), 3.99 (br. t, J=4.2, 1H); 3.00 (br.s, 1H); 2.21 (br. s, 2H); 2.05-1.96 (m, 2H); 1.96-1.84 (m, 8H). IR(cm⁻¹, KBr): 3350 (m), 2916 (s), 2850 (m), 1.647 (s), 1618 (m), 1541(s), 1498 (s), 1325 (s), 1256 (m), 1232 (m), 1159 (s), 1124 (s), 1112(s), 1086 (s), 1065 (s), 1015 (m), 978 (m), 850 (m), 834 (m).

Example 117N(7)-(1-Phenylethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (150 mg, 0.43 mmol), AMP (2.0ml), Et₃N (60 μl, 0.43 mmol), BOP reagent (193 mg, 0.43 mmol) andS-(−)-Phenylethylamine (58 μl, 0.43 mmol) furnished the title compound(130 mg, 67%). M.P.: 85-86° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.40(m, 5H); 736-7.20 (m, 4H); 5.27 (quintet, 7.2, 1H), 4.00 (t, J=5.6, 1H);2.98 (t, J=5.6, 1H), 2.19 (br. s, 2H), 2.10-1.75 (m, 10H), 1.57 (d,J=6.9, 3H). IR (cm⁻¹, KBr): 3410 (m), 2913 (s), 2845 (m), 1667 (s), 1526(s), 1498 (s), 1478 (s), 1363 (m), 1219 (m), 1160 (m), 1084 (s), 1014(m), 835 (m), 699 (m). MS (m/z): 446.10 ([M+H]⁺).

Example 118N(7)-(R-1-Phenylethyl))-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (46 μl, 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) andR-1-phenylethylamine (39 mg, 0.32 mmol) furnished the title compound (90mg, 69%). M.P.: 65-70° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.18 (m,10H); 5.35-5.18 (m, 1H); 4.00 (br. s, 1H); 2.98 (br. s, 1H); 2.19 (br.s, 2H) 2.10-1.71 (m, 10H); 1.57 (d, J=6.9, 3M). IR (cm⁻²¹, KBr): 3408(s), 3062 (w), 3029 (w), 2914 (s), 2845 (s), 1667 (s), 1596 (w), 1585(w), 1526 (s), 1498 (s), 1478 (s), 1441 (s), 1406 (m), 1363 (m), 1353(w), 1271 (m), 1232 (s), 1218 (m), 1159 (m), 1083 (s), 1033 (m), 1013(m), 933 (w), 835 (m). MS (m/z): 446.3 ([M+H]⁺).

Example 119N(7)-(1-Methyl-1-phenylethyl))-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (46 μl, 32 mmol), BOP reagent (136 mg, 0.32 mmol) andα,α-dimethylbenzylamine (48 mg, 0.36 mmol) furnished the title compound(90 mg, 67%). M.P.: 181° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.47 (hr. d,J=8.7, 4H); 7.36-7.28 (m, 5H); 7.22 (br. t, J=7.2, 1H); 3.92 (br. s,1H); 3.35 (s, 3H); 2.99 (br. s, 1H); 2.18 (br. s, 2H): 2.00-1.74 (m,10H); 1.79 (s, 6H). IR (cm⁻¹, KBr): 3407 (m), 3090 (w), 3060 (w), 3024(w), 2965 (w), 2898 (s), 2845 (m), 1675 (s), 1563 (w), 1497 (s), 1479(s), 1438 (m), 1407 (w), 1379 (w), 1362 (m), 1340 (w), 1254 (w), 1231(w), 1219 (w), 1194 (w), 1159 (w), 1085 (m), 1031 (w), 1015 (m), 834(m). MS (m/z): 460.1 (25, [M+H]⁺); 342.3 (100).

Example 120N(7)-(2-Pyridylmethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (128 mg, 0.29 mmol) and2-aminomethylpyridine ((30 μl, 0.29 mmol) gave the title compound (98mg, 78%). M.P.: 187° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.66 (t,J=6.0, 1H); 8.49 (br. d, J=5.1, 1H); 7.76 (td, 7.6, 1.8, 1H); 7.64 (d,9.0, 2H); 7.51 (d, J=9.0, 2H); 7.31 (d, J=7.6, 1H); 7.26 (m, 1H); 4.50(d, J=6.0, 2H); 3.82 (br. s, 1H); 2.98 (br. s, 1H); 2.15 (br. s, 2H),2.00-1.70 (m, 10H). IR (cm⁻¹, KBr): 2918 (m), 2847 (m), 1781 (s), 1496(s), 1443 (m), 1366 (m), 1230 (m), 1113 (m), 1089 (m), 1059 (m), 835(m). MS (m/z): 433.2 ([M+H]⁺).

Example 121N(7)-(N′-phenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.29 mmol), Et₃N (80μl, 0.58 mmol), BOP reagent (258 mg, 0.58 mmol) and phenylhydrazine (60μl, 0.58 mmol) gave the title compound (185 mg, 73%). M.P.: 103-105° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.59 (s, 1H); 7.48 (d, J=8.7, 2H); 7.33(d, J=8:7, 2H); 7.22 (t, J=7.5, 2H); 6.94 (d, J=8.7, 2H); 6.88 (t,J=7.5, 1H); 3.89 (br. t, J=4.7, 1H); 3.03 (br. s, J=3.5, 1H); 2.20 (br.s, 2H); 2.00-1.75 (m, 10H). IR (cm⁻¹, KBr): 3279 (m), 2912 (s), 2845(m), 1678 (s), 1603 (m), 1497 (s), 1467 (m), 1353 (m), 1232 (m), 1090(m), 1012 (m), 835 (m). MS (m/z): 433.1 ([M+H]⁺).

Example 122N(7)-(N′-phenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamidehydrochloride

A solution of example 121 (100 mg, 0.23 mmol) in dry ether (2.0 ml) wastreated with a saturated solution of HCl in ether (2.0 ml) at RT andstirred at RT for 1 hour and the precipitated solid was filtered toyield the title compound (90 mg, 73%). M.P.: 135-136° C. ¹H-NMR (δ ppm,DMSO-d₆, 300 MHz): 9.95 (s, 1H); 7.65 (d, J=9.0, 2H); 7.52 (d, J=9.0,2H); 7.13 (t, J=7.8, 2H); 6.74 (d, J=7.5, 2H); 6.69 (t, J=7.5, 1H); 3.67(br. s, 1H); 3.02 (br. s, 1H); 2.15 (br. s, 2H); 2.00-1.71 (m, 101-1).IR (cm⁻¹, KBr): 3419 (br. s), 3020 (m), 1642(s), 1498 (m), 1216 (m),1092 (w), 1014(w), 836 (m). MS (m/z): 433.3 ([M+H]⁺).

Example 123N(7)-(2-Chlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et₃N (90μl, 1, 0.64 mmol), BOP reagent (258 mg, 0.58 mmol) and2-chlorophenylhydrazine hydrochloride (104 mg, 0.58 mmol) furnished thetitle compound (168 mg, 62%). M.P.: 155° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.60 (s, 1H); 7.49 (d, J=8.7, 2H); 7.38-7.20 (m, 3H); 7.11 (t,J=7.2, 1H); 7.04 (dd, J=7.5, 1.5, 1H); 6.82 (t, J=7.6, 1H); 6.56 (br. s,1H); 3.90 (br. s, 1H); 3.03 (br. s, 1H); 2.20 (br. s, 2H); 2.01-1.70 (m,10H). IR (cm⁻¹, KBr): 3376 (m), 3310 (m), 2909 (m), 1683 (s), 1597 (m),1563 (w), 1498 (s), 1470 (s), 1423 (w), 1364 (m), 1212 (m), 1088 (m),1026 (m), 835 (m). MS (m/z): 467.9 ([M+H]⁺).

Example 124N(7)-(2-Chlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamidehydrochloride

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (250 mg, 0.73 mmol), DMF (3ml), Et₃N (0.12.0 ml, 0.86 mmol), BOP reagent (322 mg, 0.73 mmol) andN-(2-chlorophenyl)-N-methylhydrazine hydrochloride (220 mg, 0.80 mmol)furnished the title compound (210 mg, 60%). M.P.: 229° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.91 (s, 1H); 7.47 (d, J=8.7, 2H); 7.39 (d, J=8.1, 2H);7.34-7.20 (m, 3H); 6.99 (t, J=8.8, 1H); 3.86 (br. t, J=4.8, 1H); 3.35(s, 3H); 3.00 (br. s, 1H); 2.17 (br. s, 2H); 2.00-1.70 (m, 10H). IR(cm⁻¹, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m),1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m),1092 (s), 1083 (m), 1014 (m), 837 (s).

Example 125N(7)-[(4-chlorophenyl)amino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et₃N(0.27 ml, 1.94 mmol), BOP reagent (129 mg, 0.29 mmol) and4-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) furnished thetitle compound. (105 mg, 77%). M.P.: 208-210° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.58 (s, 1H); 7.49 (d, J=8.4, 2H); 7.33 (d, J=8.4, 2H); 7.18(d, J=8.7, 2H); 6.88 (d, J=8.7, 2H); 6.00 (br. s, 1H); 3.87 (br. s, 1H);3.03 (br. s, 1H); 2.20 (s, 2H); 2.00-1.70 (m, 10H). IR (cm⁻¹, KBr): 3282(m), 2912 (s), 2845 (m), 1670 (s), 1596 (m), 1498 (s), 1470 (s), 1253(m), 1231 (m), 1091 (s), 1013 (m), 834 (m). MS (m/z): 467.2 ([M+H]⁺).

Example 126N(7)-(2,4-Dichlorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et₃N (90μl, 0.65 mmol), BOP reagent (258 mg, 0.58 mmol) and2,4-dichlorophenylhydrazine hydrochloride (125 mg, 0.59 mmol) furnishedthe title compound (226 mg, 77%). M.P.: 214-215° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.60 (s, 1H); 7.49 (d. J=8.7, 2H); 7.40-7.22 (m, 3H);7.11 (dd, J=8.7, 2.4, 1H); 6.97 (d, J=8.7, 1H); 6.49 (br. s, 1H); 3.87(br. t, J=4.61, 1H); 3.03 (br. s, 1H); 2.20 (br. s, 2H); 2.04-1.70 (m,10H). IR (cm⁻¹, KBr): 3300 (m), 2907 (m), 2845 (m), 1681 (s), 1498 (s),1471 (s), 1232 (m), 1089 (m), 863 (m), 837(m).

Example 127N(7)-[(2,4-Dichlorophenyl-N′-methylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3.0ml), Et₃N (0.15 ml, 1.05 mmol), BOP reagent. (387 mg, 0.88 mmol) andN-(2,4-dichlorophenyl)-N-methylhydrazine (296 mg, 0.97 mmol) gave thetitle compound (220 mg, 49%). M.P.: 192° C. ¹H-NMR (δ ppm, CDCl₃, 400MHz): 8.90 (s, 1H); 7.44 (dt, J=8.8, 2.0, 2H); 7.29-7.26 (m, 4H); 7.17(dd, J=8.4, 2.4, 1H); 3.80 (br. s, 1H); 3.30 (s, 3H); 2.97 (br. s, 1H);2.15 (s, 2H); 1.86-1.75 (m, 10H). IR (cm⁻¹, KBr): 3396 (s), 2909 (s),2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s),1.438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m),837 (s). MS (m/z): 514.9 ([M+H]⁺).

Example 128N(7)-[(2,4-Dichlorophenyl-N′-methylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamidehydrochloride

A solution of example 127 (100 mg, 0.19 mmol) in ether (2.0 ml) wastreated with ether saturated with HCl (2.0 ml) and maintained at RT for1 hour and the precipitated solid was filtered to yield the titlecompound (102 mg, 95%). M.P.: 203° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz):9.86 (s, 1H); 7.53 (d, J=7.2, 2H); 7.42-7.36 (m, 3H); 7.33 (d, J=1.7,1H); 7.20 (dd, J=8.8, 1.7, 1H); 3.29 (s, 3H); 2.99 (br. s, 1H); 2.21 (s,2H); 1.88 (m, 4H); 1.88-1.80 (m, IR (cm⁻¹, KBr): 3386 m), 3197 (m), 2916(s), 2901 (s), 2845 (m), 1687 (s), 1474 (s), 1439 (s), 1260 (m), 1323(m), 1241 (m), 1124 (m), 1106 (m), 1089 (s), 1012 (m), 938 (m), 845 (m),8.29 (m). MS (m/z): 515.0 ([M−HCl+H]⁺).

Example 129N(7)-(2,4-Dichlorophenyl-N′-cyclohexylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et₃N(0.26 ml, 1.87 mmol), BOP reagent (258 mg, 0.58 mmol) andN-cyclohexyl-N-(2,4-dichlorophenyl)hydrazine hydrochloride (427 mg, 1.28mmol) gave the title compound (162 mg, 48%). M.P.: 95-96° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 8.72 (s, 1H); 7.47 (d, J=8.4, 2H); 7.42 (d, J=8.7,1H); 7.40-7.20 (m, 3H); 7.17 (dd, J=8.7, 2.4, 1H), 3.86 (br. t, J=5.2,1H); 3.75 (br. s, 1H); 2.99 (br. s, 1H); 2.17 (s, 2H), 2.00-1.70 (m,14H), 1.43-1.10 (m, 6H). IR (cm⁻¹, KBr): 3400 (m), 2919 (s), 2850 (s),1683 (s), 1564 (w), 1498 (s), 1474 (s), 1363 (m), 1233 (m), 1218 (m),1100 (m), 1062 (m), 833 (m), 753 (w). MS (m/z): 583.1 ([M+H]⁺).

Example 130N(7)-(4-Fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et₃N(0.16 ml, 1.15 mmol), BOP reagent (258 mg, 0.58 mmol) and4-fluorophenylhydrazine hydrochloride (95 mg, 0.58 mmol) gave the titlecompound (218 mg, 83%). M.P.: 125-127° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.59 (s, 1H); 7.48 (d, J=8.6, 2H); 7.32 (d, J=8.6, 2H); 7.00-6.80(m, 4H); 3.88 (br. s, 1H); 3.03 (br. s, 1H); 2.20 (br. s, 2H); 2.05-1.70(m, 10H). IR (cm⁻¹, KBr): 3263 (m), 2912 (s), 2847 (m), 1671 (s), 1508(s), 1498 (s), 1475 (m), 1234 (m), 1219 (m), 1088 (m), 884 (w), 831(m).MS (m/z): 451.0 ([M+H]⁺).

Example 131N(7)-(4-Fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamidehydrochloride.

A solution of example 130 (100 mg, 0.22 mmol) in ether (2.0 ml) wastreated with a saturated solution of HCl in ether (2.0 ml) at RT andstirred at RT for 1 hour and the precipitated solid was filtered andwashed with ether to yield the title compound (106 mg, 98%). M.P.: 175°C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 9.99 (s, 1H); 7.64 (d, J=8.5, 2H);7.50 (d, J=8.5, 2H); 6.98 (t, J=8.7, 2H); 6.74 (dd, J=8.7, 4.8, 2H);3.67 (br. s, 1H); 3.01 (br. s, 1H); 2.15 (s, 2H); 2.00-1.70 (m, 10H). IR(cm⁻¹, KBr): 3247 (br. m), 2916 (m), 2844 (m), 1694 (s), 1507 (s), 1498(s), 1234 (s), 1089 (m), 1014 (m), 990 (w), 836 (m). MS (m/z): 45.1.0([M+H]⁺).

Example 132N(7)-(2,4-Difluorophenylamino]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (200 mg, 0.58 mmol), Et₃N (22μl, 1.58 mmol), BOP reagent (258 mg, 0.58 mmol) and2,4-difluorophenylhydrazine hydrochloride (105 mg, 0.58 mmol) gave thetitle compound (225 mg, 82%). M.P.: 195-196° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.56 (s, 1H); 7.49 (d, J=9.0, 2H); 7.32 (d, J=9.0, 2H); 7.01(m, 1H); 6.86-6.74 (m, 2H); 6.24 (br. s, 1H), 3.87 (br. t, J=4.6, 1H);3.03 (br. s, 1H); 2.20 (br. s, 2H); 2.02-1.78 (m, 10H). IR (cm⁻¹, KBr):3276 (w), 2912 (m), 2846 (m), 1683 (s), 1499 (s), 1467 (m), 1137 (m),1114 (m), 848 (m), 836 (m). MS (m/z): 469.1 ([M+H]⁺).

Example 133N(7)-(3-fluorophenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3ml), Et₃N (0.22.0 ml, 1.60 mmol), BOP reagent (322 mg, 0.72 mmol) and3-fluorophenylhydrazine hydrochloride (119 μl, 0.72 mmol) yielded thetitle compound (165 mg, 50%). M.P.: 203° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.58 (s, 1H); 7.51 (d, J=9.0, 2H); 7.33 (d, J=9.0, 2H), 7.16 (q,J=6.6, 1H); 6.72-6.53 (m, 3H); 3.88 (br. s, 1H); 3.03 (br. s. 1H); 2.21(br. s, 2H); 2.05-1.80 (m, 10H). IR (cm⁻¹, KBr): 3259 (m), 2913 (s),1617 (s), 1601 (m), 1498 (s), 1442 (m), 1269 (m), 1234 (m), 1140 (m),1089 (s), 1012 (m), 832 (m), 760 (m), 679 (m). MS (m/z): 451.10([M+H]⁺).

Example 134N(7)-(3-Chloro-2-pyridylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5ml), Et₃N (68 μl, 48 mmol), BOP reagent (203 mg, 0.46 mmol) and3-chloro-2-hydrazinopyridine (69 mg, 0.48 mmol) furnished the titlecompound (170 mg, 83%). M.P.: 200-203° C. ¹H-NMR (δ ppm, DMSO-d₆, 300MHz): 9.85 (s, 1H); 8.46 (s, 1H); 8.0 (dd, J=4.5, 1.5, 1H); 7.69 (dd,J=7.5, 1.5, 1H); 7.66 (d, J=8.7, 2H); 7.51 (d, J=9.0, 2H); 6.75 (dd,J=7.8, 4.8, 1H); 3.73 (br. s, 1H); 3.02 (br. s, 1H); 2.15 (br. s, 2H);2.00-1.70 (m, 10H). IR (cm⁻¹, KBr): 3382 (m), 2902 (m), 2846 (m), 1683(m), 1664 (m); 1589 (s), 1498 (s), 1455 (s), 1401 (m), 1229 (m), 1117(m), 1089 (m), 1030 (m), 833 (m). MS (m/z): 468.10 ([M+H]⁺).

Example 135N(7)-(5-Chloro-2-pyridylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5ml), Et₃N (68 μl, 0.48 mmol), BOP reagent (203 mg, 0.46 mmol) and5-chloro-2-hydrazinopyridine (70 mg, 0.49 mmol) furnished the titlecompound (170 mg, 83%). M.P.: 130-135° C. ¹H-NMR (δ ppm, DMSO-d₆, 300MHz): 10.02 (s, 1H); 8.62 (s, 1H); 8.06 (d, J=2.4, 1H); 7.66 (d, J=8.5,2H); 7.60 (dd, J=8.7, 2.5, 1H); 7.51 (d, J=8.5, 2H); 6.60 (d, J=8.7,1H); 3.69 (br. s, 1H); 3.01 (br. s, 1H); 2.15 (br. s, 2H); 2.00-1.70 (m,10H). IR (cm⁻¹, KBr): 3285 (m), 2909 (s), 2847 (m), 1671 (s), 1595 (m),1498 (s), 1477 (s), 1364 (m), 1255 (m), 1233 (m), 1089 (m), 1012 (m),832 (m). MS (m/z): 468.10 ([M+H]⁺).

Example 136N(7)-(2-Phenylethyl)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), Et₃N (40μl, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and phenethylamine (36μl, 0.29 mmol) furnished the title compound (105 mg, 81%). M.P.: 148° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.46 (d, J=8.7, 2H); 7.35-7.18 (m, 7H);7.07 (br. t, J=7.5, 1H); 3.99 (br. t, J=4.7, 1H); 3.63 (q, J=7.5, 2H);3.00 (br. t, J=4.7, 1H); 2.90 (t, J=7.5, 2H); 2.20 (br. s, 2H);2.05-1.95 (m, 2H); 1.94-1.75 (m, 8H). IR (cm⁻¹, KBr) 3398 (m), 2913 (s),2843 (m), 1673 (s), 1538 (s), 1498 (s), 1483 (s), 1382 (m), 1231 (m),1086 (m), 998 (m), 839 (m). MS (m/z): 446.1 ([M+H]⁺).

Example 137N(7)-(N′,N′-Diphenylamino)-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3ml), Et₃N (0.27 ml, 1.94 mmol), BOP reagent (387 mg, 0.88 mmol) andN,N-diphenylhydrazine hydrochloride (192 mg, 0.87 mmol) gave the titlecompound (370 mg, 83%). M.P.: 214° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):9.04 (s, 1H); 7.47 (d, J=8.4, 2H); 7.33 (d, J=8.4, 2H); 7.28-7.20 (m,8H); 7.00 (t, J=8.4, 2H); 3.94 (br. s, 1H); 3.03 (br. s, 1H); 2.20 (s,2H); 2.05-1.80 (m, 101-1). IR (cm⁻¹, KBr): 3384 (m), 2912 (m), 2900 (m),1702 (s), 1591 (m), 1497 (s), 1466 (m), 1277 (w), 1235 (w), 1092 (m),1012 (w). MS (m/z): 509.4 ([M+H]⁺).

Example 138N7-[1-(2-Chlorophenyl)ethyl]-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (141 mg, 0.31 mmol) and(±)-1-(2-chlorophenyl)ethylamine (48 μl, 0.29 mmol) furnished the titlecompound (104 mg, 77° A)). M.P.: 198° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.48-7.18 (m, 8H); 5.27 (quintet, J=7.2, 1H); 3.99 (br. s, 1H); 2.98(br. s, 1H); 2.18 (br. s, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J=7.2, 3H).IR (cm⁻¹, KBr): 3400 (m), 2915 (s), 2880 (s), 1666 (s), 1498 (s), 1528(s), 1480 (s), 1362(m), 1229 (m), 1085 (m), 1012(w)_(;) 834 (m), 696(m).

Example 139N(7)-Benzyl-5-(4′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 10:1 using intermediate 2 (100 mg, 0.29 mmol), DMF (1 ml),triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) andbenzylamine (0.031 ml, 0.291 mmol) to give the title compound (72 mg,57%). M.P.: 164-166° C. ¹H-NMR (δ ppm, CDCl₃): 7.45 (d, J=8.4, 2H);7.39-7.21 (m, 7H); 4.58 (d, J=6.0, 2H); 4.02 (t, J=5.4, 1H); 3.00 (br.t, J=4.7, 1H); 2.20 (br. d, 2H); 2.04-1.77 (m, 10H). IR (cm⁻¹, KBr):3471(m), 3403 (m), 2919 (s), 2884 (n1), 1672 (s), 1534 (m), 1499 (s).

Example 140N(7)-Piperidino-5-(4-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine(0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and1-aminopiperidine (0.031 ml, 0.291 mmol) to give the title compound (85mg, 68%). M.P.: 185-188° C. ¹H-NMR (δ ppm, CDCl₃): 7.67 (br. s, 1H);7.46 (d, J=8.7, 2H); 7.29 (d, J=8.7, 2H); 3.99 (br. t, J=5.4, 1H); 2.99(br. t, 1H); 2.85 (br. s, 4H); 2.19 (br. s, 2H); 2.06-1.69 (m, 14H);1.44-1.38 (m, 2H). IR (cm⁻¹, KBr): 3436 (m), 3320 (m); 2921 (s), 2853(m), 1694 (m), 1668 (s), 1499 (m).

Example 1417-(4′-Chlorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-dien-5-yl-piperidinoethanone

The title compound was synthesized as per the procedure described forexample 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine(0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and piperidine(0.028 ml, 0.291 mmol) to give the title compound (85 mg, 71%). M.P.:151-153° C. ¹H-NMR (δ ppm, CDCl₃): 7.43 (d, J=9.0); 7.31 (d, J=9.0);3.70 (br. s, 2H); 3.55 (t, J=5.1, 2H); 3.00-3.10 (m, 2H); 2.21 (br. s,2H); 2.05-1.78 (m, 10H); 1.75-1.50 (m, 18H). IR (cm⁻¹, KBr): 2913 (m),1634 (s), 1498 (m).

Example 142N(7)-Phenyl-5-(4′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine(0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and aniline (0.026ml, 0.29 mmol) to give the title compound (95 mg, 77%). M.P.: 188-190°C. ¹H-NMR (δ ppm, CDCl₃): 8.78 (br. s, 1H); 7.67 (d, J=8.4, 2H); 7.50(d, J=8.7, 2H); 7.30-7.37 (m, 4H); 7.12 (t, J=8.4, 1H); 4.05 (t, J=5.4,1H); 3.02 (t, J=4.8, 1H); 2.22 (br. s, 2H); 2.10-1.75 (m, 101-1). IR(cm⁻¹, KBr): 3365 (m), 2915 (m), 2844 (m), 1682 (s), 1532 (s), 1498 (s).

Example 143N(7)-Piperidino-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (42 μl, 0.31 mmol), BOP reagent (135 mg, 0.31 mmol) andN-aminopiperidine ((33 μl, 0.31 mmol) gave the title compound (96 mg,73%). M.P.: 215° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (br. s, 1H);7.49-7.40 (m, 1H); 7.05-6.95 (m, 2H); 3.96 (br. s, 1H); 2.86 (br. s,4H); 2.65 (br. s, 1H); 2.18 (br. s, 2H), 2.04-1.90 (m, 2H); 1.85-1.62(m, 12H); 1.42 (br. s, 2H). IR (cm⁻¹, KBr): MS (m/z): 427.20 ([M+H]⁺).

Example 144N(7)-(Adamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title, compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0ml), Et₃N(72 μl, 0.52 mmol), BOP reagent (192 mg, 0.44 mind) and1-adamantylamine (65 mg, 0.44 mmol) furnished the title compound (156mg, 75%). M.P.: 221-224° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.38(m, 1H); 7.06-6.93 (m, 2H); 6.68 (br. s, 1H); 3.97 (br. s, 1H); 3.35(br. s, 3H); 2.22-1.54 (m, 27H). IR (cm⁻¹, KBr): 3394 (m), 2915 (s),2850 (s), 1669 (s), 1611 (m), 1566 (m), 1520 (s), 1483 (m), 1440 (m),1359 (m), 1353 (m), 1273 (m), 1225 (m), 1220 (m), 1140 (m), 1092 (m),1082 (m), 966 (m), 850 (m). MS (m/z): 478.2 ([M+H]⁺).

Example 145N(7)-(1S,2endo-1,3,3-Trimethyl-bicyclo[2.2.1]hept-2-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0ml), Et₃N(72 μl, 0.52 mmol), BOP reagent (192 mg, 0.44 mmol) and2-amino-1,3,3-Trimethyl-bicyclo[2.2.1]heptane (66 mg, 0.44 mmol)furnished the title compound (176 mg, 84%). M.P.: 235-23° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.51-7.42 (m, 1H); 7.07-6.95 (m, 3H); 3.98 (br. s,1H); 3.72 (d, J=6.0, 1H); 2.67 (br. s, 1H); 2.18 (br. s, 2H); 2.06-1.54(m, 13H); 1.54-1.28 (m, 2H); 1.28-1.14 (m, 2H); 1.16, 1.10, 0.85 (3s,9H). IR (cm⁻¹, KBr): 3419 (s), 2927 (s), 2905 (s), 2870 (m), 1669 (s),1567 (m), 1515 (s), 1480 (m), 1442 (m), 1366 (m), 1.275 (m), 1226 (m),1226 (m), 1097 (m), 1080 (m), 967 (m), 858 (m), 845 (m). MS (m/z): 480.3([M+H]⁺).

Example 146N(7)-(S-1-phenylethyl))-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5ml), Et₃N(75 μl, 0.51 mmol), BOP reagent (214 mg, 0.53 mmol) andS-1-phenylethylamine (65 μl, 0.50 mmol) furnished the title compound(120 mg, 58%). M.P.: 123-128° C. 7.50-7.13 (m, 7H); 7.06-6.94 (m, 2H);5.27 (quintet, J=7.2, 1H); 3.97 (br. s, 1H); 2.65 (br. s, 1H); 2.17 (br.s, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J=7.2, 3H). IR (cm⁻¹, KBr): 3404(m), 2911 (s), 2846 (m), 1668 (s), 1519 (s), 1480 (m), 1439 (m), 1367(w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (m), 966 (w), 854 (m).MS (m/z): 448.2 ([M+H]⁺).

Example 147N(7)-(R-1-phenylethyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5ml), Et₃N(75 μl, 0.51 mmol), BOP reagent (214 mg, 0.53 mmol) andR-1-phenylethylamine (65 μl, 0.50 mmol) furnished the title compound(125 mg, 61%). M.P.: 123-128° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.50-7.12 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintet, J=7.5, 1H); 3.97(br. s, 1H); 2.65 (br. s, 1H); 2.17 (br. s, 2H); 2.07-1.70 (m, 10H);1.56 (d, J=7.5, 3H). JR (cm⁻¹, KBr): 3404 (m), 2911 (s), 2846 (m), 1669(s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227(m), 1145 (m), 1081 (w), 966 (m), 853 (m). MS (m/z): 448.2 ([M+H]⁺).

Example 148N(7)-(1-Methyl-1-phenylethyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5ml), Et₃N(75 μl, 0.51 mmol), BOP reagent (214 mg, 0.53 mmol) andα,α-dimethylbenzylamine (68 mg, 0.51 mmol) furnished the title compound(70 mg, 33%). M.P.: 150-152° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.60-7.41 (m, 3H); 7.33 (t, J=7.2, 2H); 7.22 (t, J=7.2, 1H); 7.05-6:95(m, 2H); 3.89 (br. s, 1H); 2.65 (br. s, 1H); 2.16 (br. s, 2H); 2.00-1.54(m, 10H); 1.78 (s, 6H). IR (cm⁻¹, KBr): 3419 (m), 2906 (m), 1678 (s),1519 (s), 1276 (m), 1261 (m), 1134 (m), 968 (m), 848 (m). MS (m/z):462.2 (100, [M+H]⁺), 344.1 (90).

Example 149N(7)-(2-Chlorobenzyl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (128 mg, 0.29 mmol) and2-chlorobenzylamine ((55 μl, 0.46 mmol) gave the title compound (152 mg,71%). M.P.: 136° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.51-7.39 (m, 3H);7.35 (dd, J=7.5, 2.4, 1H); 7.24-7.18 (m, 2H); 7.05-6.95 (m, 2H); 4.67(d, J=6.0, 2H); 3.98 (t, J=5.4, 1H); 2.67 (br. s, 1H); 2.19 (br. s, 2H),2.10-1.95 (m, 2H); 1.95-1.65 (m, 10H). IR (cm⁻¹, KBr): 3329 (m), 2918(s), 2849 (m), 1648 (s), 1537 (m), 1515 (m), 1442 (m), 1220 (m), 1083(m), 1051 (m), 750 (m). MS (m/z): 468.0 ([M+H]⁺).

Example 150N(7)-(2,4-Dichlorophenylamino)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (150 mg, 0.46 DMF (2.0 ml),Et₃N (63 μl, 0.46 mmol), BOP reagent (203 mg, 0.46 mmol) and2,4-dichlorophenylhydrazine hydrochloride (98 mg, 0.46 mmol) furnishedthe title compound (107 mg, 47%). M.P.: 162° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.70 (br. s, 1H); 7.48 (m, 1H); 7.30 (d, J=1.2, 1H); 7.16-6.96(m, H); 3.87 (br. s, 1H); 2.71 (br. s, 1H); 2.19 (br. s, 2H), 2.05-1.70(m, 10H). IR (cm⁻¹, KBr): 3394 (br. s, s), 2916 (s), 1683 (s), 1519 (m),1274 (m), 1216 (m), 1145 (s), 1118 (s), 1099 (m), 967 (m), 850 (m), 817(m). MS (m/z): 503.0 ([M+H]⁺).

Example 151N(7)[1-(2-Chlorophenyl)ethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (141 mg, 0.31 mmol) and(±)-1-(2-chlorophenyl)ethylamine (48 μl, 0.29 mmol) furnished the titlecompound (60 mg, 41%). M.P.: 143-146° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.46-7.14 (m, 5H); 7.04-6.94 (m, 2H); 5.26 (quintet, J=7.2, 1H); 3.97(br. s, 1H); 2.65 (br. s, 1H); 2.17 (br. s, 2H); 2.04-1.70 (m, 10H);1.56 (d, J=7.2, 3H). IR (cm⁻¹, KBr): 3419 (m), 2915 (s), 2847 (m), 1666(s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1368(w), 1353(w), 1273 (m),1219(m), 1144 (m), 1082 (m), 967 (m), 852 (m).

Example 152N(7)-[(S)-1-Phenylpropyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (141 mg, 0.31 mmol) and(s)-1-phenylpropylamine (41 μl, 0.29 mmol) furnished the title compound(84 mg, 63%). M.P.: 127-129° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.50-7.10 (m, 1H); 7.34-7.15 (m, 6H); 7.05-6.90 (m, 2H); 4.99 (q, J=7.5,1H); 3.96 (t. J=6.2, 1H); 2.64 (br. s, 1H); 2.16 (br. s, 2H); 2.04-1.70(m, 12H); 0.94 (t, J=7.2, 3H). IR (cm⁻¹, KBr): 3410 (m), 3325 (m), 2916(s), 2848 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1367(w), 1353 (w), 1273 (m), 1226 (m), 1217 (m), 1144 (m), 1083 (m),1030(w), 966 (w), 966 (m), 852 (w), 756 (s), 700 (m). MS (m/z): 462.1([M+H]⁺).

Example 153N7-[1-(2-Chlorophenyl)-1-methylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (45 μl, 0.31 mmol), BOP reagent (141 mg, 0.31 mmol) and2-(2-chlorophenyl)-prop-2-ylamine (73 mg, 0.43 mmol) furnished the titlecompound (95 mg, 66%). M.P.: 145-147° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.57 (dd, J=7.5, 1.2, 1H); 7.52-7.39 (m, 2H); 7.32 (dd, J=7.8, 1.5, 1H);7.26-7.20 (m, 1H); 7.16 (td, J=7.8, 1.5, 1H), 7.08-6.94 (m, 2H); 3.82(br. t. J=6.2, 1H); 2.64 (br. s, 1H); 2.14 (br. s, 2H); 1.95-1.74 (m,10H); 1.38 (s, 6H). IR (cm⁻¹, KBr): 3419 (m), 2919 (m), 2892 (m), 2841(m), 1674 (s), 1515 (s), 1441 (m), 1384 (w), 1362 (w), 1274 (m), 1249(m), 1226 (m), 1139 (m), 1083 (m), 1039 (m), 967 (m), 843 (m), 727 (n).MS (m/z): 496.2 ([M×H]⁺).

Example 154Methyl(2R)-2-[7-(2,4-difluorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),5-dien-5-ylcarboxamido]-2-phenylethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0ml), Et₃N (193 μl, 1.39 mmol), BOP reagent (282 mg, 0.64 mmol) and(R)-(+)-2-phenylglycine methyl ester hydrochloride (117 mg, 0.58 mmol)furnished the title compound (140 mg, 57%). M.P.: 138-141° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.78 (d, J=7.2, 1H); 7.49-7.30 (m, 6H); 7.10-6.90(m, 2H); 5.72 (d, J=7.5, 1H); 3.91 (t. J=6.1, 1H); 3.74 (s, 3H); 2.66(br. s, 1H); 2.16 (br. s, 2H); 2.00-1.70 (m, 10H). IR (cm⁻¹, KBr): 3411(m), 2915 (s), 2848 (m), 1744 (s), 1671 (s), 1613 (m), 1570 (m), 1519(m), 1478 (m), 1478 (m), 1441 (m), 1352 (w), 1367 (w), 1352 (w), 1322(m), 1273 (m),1209 (m), 1081 (m), 967 (w), 851 (w), 754 (m), 698 (m). MS(m/z): 492.1 ([M+H]⁺).

Example 155Methyl(2S)-2-[7-(2,4-difluorophenyl)-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-461),5-dien-5-ylcarboxamido]-2-phenylethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (500 mg, 1.45 mmol), DMF (4.0ml), Et₃N (480 μl, 3.48 mmol), BOP reagent (706 mg, 1.59 mmol) and(S)-(+)-2-phenylglycine methyl ester hydrochloride (293 mg, 1.45 mmol)furnished the title compound (525 mg, 73%). M.P.: 132-135° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.78 (d, J=6.9, 1H); 7.52-7.25 (m, 6H); 7.05-6.90(m, 2H); 5.71 (d, J=7.2, 1H); 3.90 (t. J=6.2, 1H); 3.74 (s, 3H); 2.66(br. s, 1H); 2.16 (br. s, 2H); 2.04-1.70 (m, 10H). IR (cm⁻¹, KBr): 3432(m), 3413 (m), 2919 (s), 2849 (m), 1755 (s), 1740 (s), 1672 (s), 1614(m), 1570 (m), 1522 (s), 1479 (m), 1439 (m), 1223 (m), 1308 (m), 1326(m), 1274 (m), 1259 (m), 1207 (m), 1161 (m), 1143 (m), 1082 (m), 1029(w), 967 (m), 845 (m), 697. MS (m/z): 492.1 ([M+H]⁺).

Example 156N7-(3-Hydroxyadamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0ml), Et₃N (88 μl, 0.63 mmol), BOP reagent (282 mg, 0.63 mmol) and3-amino-1-adamantanol (97 mg, 0.58 mmol) furnished the title compound(143 mg, 51%). M.P.: 240-243° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.48-7.33 (m, 1H); 7.05-6.94 (m, 2H); 6.74 (br. s, 1H); 3.94 (br. s,1H); 2.64 (br. s, 1H), 2.28 (br. s, 2H); 2.17 (br. s, 2H); 2.11 (br. s,2H); 2.04-1.56 (m, 21H). IR (cm⁻¹, KBr): 3385 (m), 2911 (s), 2849 (m),1657 (s), 1610 (w), 1560 (w), 1520 (m), 1482 (m), 1441 (w), 1441 (w),1362 (w), 1352 (w), 1273 (w), 1253 (w), 1227 (m), 1150 (m), 1132 (m),1101 (w), 1084 (w), 1048 (w), 1025 (w), 966 (m), 872 (m). MS (m/z):494.0 ([M+H]⁺).

Example 157N(7)-(1-Methyl-1-phenylethyl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (148 mg, 0.33 mmol) andα,α-dimethylbenzylamine (49 mg, 0.36 mmol) furnished the title compound(92 mg, 68%). M.P.: 180-182° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.47 (d,J=7.8, 2H); 7.38-7.14 (m, 8H); 3.91 (br. s, 1H); 2.95 (br. s, 1H); 2.17(br. s, 2H); 1.97-1.76 (m, 16H). IR (cm⁻¹, KBr): 3412 (m), 3064 (w),2981 (w), 2916 (s), 2846 (m), 1672 (s), 1565 (w), 1512 (s), 1482 (m),1439 (m), 1382 (w), 1363 (w), 1257 (m), 1215 (s), 1155 (m), 1084 (m),844 (m). MS (m/z): 443.9 (100%), 444.9 ([M+H]⁺).

Example 158N(7)-(Adamantan-1-yl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 4 (150 mg, 0.46 mmol), DMF (1.5ml), Et₃N(76 μl, 0.55 mmol), BOP reagent (223 mg, 0.50 mmol) and1-adamantylamine (69 mg, 0.46 mmol) furnished the title compound (150mg, 71%). M.P.: 214-216° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.36-7.26(m, 2H); 7.20-7.12 (m, 2H); 6.73 (br. s, 1H); 3.99 (br. s, 1H); 2.94(br. s, 1H), 2.19-1.55 (m, 27H). IR (cm⁻¹, KBr): 3392 (m), 2905 (s),2847 (m), 1671 (s), 1560 (w), 1529 (m), 1512 (s), 1481 (m), 1454 (w),1441 (w), 1357 (m), 1219 (m), 1092 (m), 841 (m). MS (m/z): 460.3([M+H]⁺).

Example 158aN7-(Adamantan-2-yl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 4 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (124 μl, 0.88 mmol), BOP reagent (170 mg, 0.38 mmol) and2-adamantylamine hydrochloride (103 mg, 0.55 mmol) furnished the titlecompound (120 mg, 80%). M.P.: 196-1.98° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.69-7.63 (m, 2H); 7.17 (t, J=8.1, 2H); 4.23 (d, J=8.4, 1H); 3.75(br. s, 1H); 3.65 (br. s, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H),1.26-1.21 (m, 2H). IR (cm⁻¹, KBr): 3414 (s), 2979 (w), 2901 (s), 285.1(s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347(w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m),1091 (m), 953 (w),833 (m). MS (m/z): 406.2 ([M+H]⁺).

Example 159N7-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-5-(4-fluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5ml), Et₃N (103 □l, 0.73 mmol), BOP reagent (142 mg, 0.32 mmol) and1S,2endo-amino-1,3,3-trimethyl-bicyclo[2.2.1]heptane (86 mg, 0.46 mmol)furnished the title compound (101 mg, 71%). M.P.: 139-141° C. ¹H-NMR, δppm, CDCl₃, 300 MHz): 7.38-7.31 (m, 2H); 7.21-7.04 (m, 3H); 4.00 (br. s,1H); 3.73 (d, J=9.6, 1H); 2.98 (br. s, 1H), 2.19 (br. s, 1H), 2.05-1.66(m, 14H), 1.51-1.39 (m, 2H), 1.25-1.08 (m, 1H), 1.21, 1.01, 0.85 (3s,9H). IR (cm⁻¹, KBr): 3418 (s), 2927 (s), 2904 (s), 2870 (m), 1670 (s),1607 (w), 1560 (m), 1510 (s), 1525 (s), 1479 (m), 1440 (m), 1375 (w),1355 (w), 1365 (w), 1220 (m), 1159 (m),1151 (m), 1089 (m), 1029 (m), 838(m). MS (m/z): 462.3 ([M+H]⁺).

Example 160N(7)-Piperidino-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (46 μl, 0.33 mmol), BOP reagent (137 mg, 0.31 mmol) and1-aminopiperidine (35 μl, 0.33 mmol) yielded the title compound (70 mg,56%). M.P.: 228-232° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (br. s,1H); 7.28 (d, J=9.0, 2H); 7.23 (d, J=9.0, 2H); 3.99 (br. t, J=4.83, 1H);2.99 (br. s, 1H); 2.85 (br. s, 4H); 2.42 (s, 3H); 2.18 (br. s, 2H);2.04-1.95 (m, 2H); 1.95-1.65 (m, 12H); 1.41 (br. s, 2H). IR (cm⁻¹, KBr):3306 (m), 2949 (s), 2937 (s), 2911 (s), 2849 (s), 2790 (m), 1690 (s),1563 (w), 1518 (s), 1488 (m), 1462 (m), 1349 (m), 1216 (m), 1127 (m),1108 (m), 987 (m), 830 (m). MS (m/z): 405.20 ([M+H]⁺).

Example 161N(7)-(2,4-Dichlorophenylamino)-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (46 μl, 0.33 mmol), BOP reagent (137 mg, 0.31 mmol) and2,4-dichlorophenylhydrazine hydrochloride (70 mg, 0.32 mmol) gave thetitle compound (110 mg, 73%). M.P.: 208-215° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 9.42 (br. s, 1H); 7.38-7.20 (m, 7H); 7.14-7.00 (m, 1H); 3.96(br. s, 1H); 3.04 (br. s, 1H); 2.45 (s, 3H); 2.40-1.80 (m, 12H). IR(cm⁻¹, KBr): 3314 (m), 3247 (m), 2914 (s), 2846 (m), 1674 (s), 1661 (s),1515 (s), 1477 (s), 1478 (s), 1390 (m), 1363 (m), 1254 (m), 1235 (m),1216 (m), 1089 (m), 1079 (m), 862 (m), 825 (s). MS (m/z): 481.10([M+H]⁺).

Example 162N(7)-(2-Chlorobenzyl)-5-(4-methylphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (46 μl, 0.33 mmol), BOP reagent (1.37 mg, 0.31 mmol) and2-chlorobenzylamine (40 μl, 0.36 mmol) furnished the title compound (80mg, 58%). M.P.: 127-130° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (br. s,1H); 7.48 (br. d, J=6.9, 1H); 7.38-7.16 (m, 7H); 4.68 (d, J=6.0, 2H);4.02 (br. t, J=4.6, 1H); 3.00 (br. s, 1H); 2.42 (s, 3H); 2.20 (br. s,2H); 2.10-1.70 (m, 10H). IR (cm⁻¹, KBr): 3410 (m), 2915 (s), 2904 (s),2842 (m), 1663 (s), 1526 (s), 15.17 (s), 1478 (s), 1465 (s), 1439 (s),1365 (m), 1352 (m), 1.232 (m), 1215 (m), 1085 (m), 829 (m), 756 (m). MS(m/z): 446.10 ([M+H]⁺).

Example 163N(7)-Piperidino-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (2.0ml), Et₃N (44 μl, 0.32 mmol), BOP reagent (129 mg, 0.32 mmol) and1-aminopiperidine (29 μl, 0.29 mmol) gave the title compound (65 mg,58%). M.P.: 156° C. (fuses). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.22 (d,J=6.9, 3H); 6.98 (d, J=6.9, 2H); 3.86 (br. s, 3H); 3.74 (br. s, 1H);3.01 (br. s, 1H), 2.38-1.70 (m, 20H). IR (cm⁻¹, KBr): 3284 (m), 2917(s), 2849 (s), 1655 (s), 1609 (m), 1519 (s), 1471 (s), 1440 (s), 1353(m), 1298 (m), 1256 (s), 1231 (s), 1147 (m), 1071 (m), 1010 (m), 891(m), 814 (s). MS (m/z): 421.20 ([M+H]⁺).

Example 164N7-(2-Chlorobenzyl)-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (44 μl, 0.32 mmol), BOP reagent (129 mg, 0.32 mmol) and2-chlorobenzylamine (32 μl, 0.27 mmol) yielded the title compound (85mg, 69%). M.P.: 178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.45 (m,2H); 7.37-7.10 (m, 5H); 6.98 (br. d, J=7.5, 2H); 4.67 (br. s, 2H); 4.00(br. s, 1H); 3.86 (br. s, 3H); 2.96 (br. s, 1H); 2.19 (br. s, 2H),2.10-1.40 (m, 10H). IR (cm⁻¹, KBr): 3395 (s), 2904 (m), 2848 (m), 1667(s), 1531 (s), 1515 (s), 1444 (s), 1353 (s), 1242 (s), 1230 (s), 1222(s), 1231 (s), 1162 (m), 985 (m), 839 (m). MS (m/z): 462.10 ([M+H]⁺).

Example 165N(7)-(2,4-Dichlorophenylamino)-5-(4-methoxyphenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(3),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 6 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (44 μl, 0.32 mmol), BOP reagent (125 mg, 0.28 mmol) and2,4-dichlorophenylhydrazine hydrochloride (57 mg, 0.27 mmol) furnishedthe title compound (78 mg, 56%). M.P.: 199° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.75 (br. s, 1H); 7.36-7.27 (m, 3H); 7.10 (dd, J=9.0, 1.8, 1H);7.06-6.94 (d, J=9.0, 1H); 6.97 (br. s, 1H); 6.50 (br. s, 1H); 3.87 (br.s, 4H); 3.00 (br. s, 1H); 2.19 (br. s, 2H), 2.02-1.80 (m, 10H). IR(cm⁻¹, KBr): 3359 (s), 3020 (w), 2912 (s), 2844 (m), 1678 (s), 1517 (s),1473 (s), 1247 (s), 1229 (s), 1075 (M), 1020 (m), 837 (s). MS (m/z):497.10 ([M+H]⁺).

Example 166N(7)-Piperidino-5-[(2-chlorophenyl)phenyl]-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

A soln. of example 101 (170 mg, 0.36 mmol) in dioxane (4.0 ml) wastreated with 4-chlorophenyl boronic acid (62 mg, 0.33 mmol),Pd(PPh₃)₂Cl₂ (6 mg, 0.009 mml) and sodium carbonate (115 mg, 1.08 mmol)and refluxed for 7 h. The solvent was evaporated and residue dissolvedin AcOEt and washed with water. The organic layer was dried over Na₂SO₄,filtered and the solvent was removed. The residue was subjected to FC togive ca. 70% (as analysed by HPLC) pure product which was furtherpurified by preparative TLC to afford the title compound (70 mg, 39%).HPLC-purity: 99.8%. M.P.: 206° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.59-7.38 (m, 4H); 7.27 (d, 8.4, 2H); 6.99 (d, 8.4, 2H); 3.84 (br. s,1H); 3.35 (s, 3H); 2.89 (br. s, 4H); 2.35 (br. s, 1H); 2.00-1.70 (m,18H). MS (m/z): 501.2 ([M+H]⁺).

Example 167N(7)-[(2,4-Dichlorophenyl)amino]-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101 using intermediate 7 (100 mg, 0.33 mmol), DMF(1.0 ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (151 mg, 0.34 mmol) and2,4-dichlorophenylhydrazine hydrochloride (77 mg, 0.36 mmol) to give thetitle compound (110 mg, 71%). M.P.: 166-170° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.60 (s, 1H); 7.56-7.42 (m, 3H); 7.39 (dd, J=7.5, 2.1, 2H);7.29 (d, d=2.2, 2H); 7.12 (dd, J=9.0, 2.2, 1H); 6.80 (d, J=9.0, 1H);6.55 (br. s, 1H); 3.90 (t, J=6.0, 1H), 3.15 (br. s, 1H); 2.20 (s, 2H);2.04-1.74 (m, 10H). IR (cm⁻¹, KBr): 3371 (s), 3307 (m), 2910 (s), 2848(m), 1683 (s), 1596 (m), 1564 (m), 1501 (m), 1463 (s), 1450 (s), 1393(m), 1361 (m), 1231 (m), 1214 (m), 1075 (m), 1018 (m), 872 (m). MS(adz): 467.1 ([M±H]⁺).

Example 168N(7)-Phenyl-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml),triethylamine (0.05 ml, 0.35 mmol), BOP reagent (151 mg, 0.34 mmol) andaniline (33 μl, 0.35 mmol) to give the title compound (70 mg, 56%).M.P.: 178-181° C. ¹H-NMR (δ ppm, CDCl₃): 8.82 (br. s, 1H); 7.67 (d,J=7.8, 2H); 7.56-7.29 (m, 7H); 7.09 (t, J=7.5); 4.06 (br. t, J=5, 1H);3.07 (br. t, J=4.3, 1H); 2.22 (br. s, 2H); 2.09-1.98 (m, 2H); 1.98-1.76(m, 8H). (cm⁻¹, KBr): 3449 (br., m), 3384(m), 2922 (m), 2904 (m), 2844(m), 1689 (s), 1601 (m), 1591 (m), 1528 (s), 1502 (s).

Example 169N(7)-piperidino-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 7 (155 mg, 0.5 mmol), DMF (2 ml),triethylamine (77 μl, 0.55 mmol), BOP reagent (235 mg, 0.53 mmol) and1-aminopiperidine (60 μl, 0.55 mmol) to give the title compound (120 mg,61%). ¹H-NMR (δ ppm, CDCl₃): 7.69 (br. s, 1H); 7.53-7.32 (m, 5H); 4.00(br. t, J=5.5, 1H); 3.02 (br. t, J=4.6, 1H); 2.84 (br. t, J=4.8, 4H);2.19 (br. s, 2H); 2.05-1.68 (m, 14H); 1.44-1.36 (m, 2H). IR (cm⁻¹, KBr):3345 (m), 3306(m), 2941 (s), 2920 (s), 2906 (s), 1687 (s), 1525 (m),1500 (m).

Example 170N(7)-Benzyl-5-phenyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml),triethylamine (0.05 ml, 0.35 mmol), BOP reagent (151 mg, 0.34 mmol) andbenzylamine (39 μl, 0.35 mmol) to give the title compound (70 mg, 55%).M.P.: 137-139° C. ¹H-NMR (δ ppm, CDCl₃): 7.51-7.21 (m, 11. H); 4.58 (d,J=5.7, 2H); 4.03 (br. t, JK=5, 1H); 3.03 (br. t, J=4.3, 1H); 2.20 (br.s, 2H); 2.08-1.98 (m, 2H); 1.98-1.76 (m, 8H). IR (cm⁻¹, KBr): 3405 (m),3361(m), 2916 (s), 2900 (s), 2844 (m), 1659 (s), 1541 (s), 1504 (m).

Example 171N(7)-phenyl-6,7-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-dien-5-yl-piperidinomethanone

The title compound was synthesized as per the procedure described forexample 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 ml),triethylamine (0.05 ml, 0.35 mmol), BOP reagent (151 mg, 0.34 mmol) andpiperidine (36 μl, 0.35 mmol) to give the title compound (50 mg, 50%).M.P.: 123-125° C. ¹H-NMR (δ ppm, CDCl₃): 7.49-7.35 (m, 5H); 3.71 (br. s,2H); 3.57 (t, J=5.4, 2H); 3.11 (br. s, 1H); 3.05 (br. s, 1H); 2.21 (br.s, 2H); 2.04-1.74 (m, 10H); 1.70-1.51 (m, 8H). IR (cm⁻¹, KBr): 2916 (s),2845 (m), 1630 (s), 1597 (m), 1500 (m).

Example 172N(7)-(4-Fluorobenzyl)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0ml), Et₃N (41 μl, 0.29 mmol), BOP reagent (123 mg, 0.28 mmol) and4-fluorobenzylamine (37 mg, 33 μl, 0.29 mmol) gave the title compound(95 mg, 74%). M.P.: 68-70° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.54 (d,J=2.4, 1H); 7.38-7.15 (m, 5H); 7.00 (t, J=8.4, 2H); 4.53 (dd, J=14.1,5.7, 2H)); 3.98 (br. s, 1H), 2.53 (br. s, 1H); 2.18 (br. s, 2H);2.00-1.61 (m, 101-1). IR (cm⁻¹, KBr): 3415 (m), 3307 (m), 2913 (s), 2846(m), 1667 (s), 1537 (s), 1509 (s), 1498 (s), 1441 (m), 1352 (m), 1220(s), 1.1.56 (m), 1088 (m), 1071 (m), 824 (s). MS (m/z): 484.1 ([M+H]⁺).

Example 173N(7)-Phenylamino-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0ml), Et₃N (41 μl, 0.29 mmol), BOP reagent (123 mg, 0.29 mmol) andphenylhydrazine (29 μl, 0.29 mmol) gave the title compound (80 mg, 65%).M.P.: 162-163° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.53 (s, 1H); 7.59 (d,J=2.4, 1H); 7.42 (dd, J=8.4, 2.1, 1H); 7.35 (d, J=8.4, 1H); 7.22 (t,J=8.4, 2H); 6.95 (d, J=−8.4, 2H); 6.89 (t, J=7.2, 1H); 3.87 (br. s, 1H),2.57 (br. s, 1H); 2.18 (br. s, 2H); 2.00-1.67 (m, 10H). IR (cm⁻¹, KBr):3292 (m), 2911 (s), 2845 (m), 1670 (s), 1603 (m), 1566 (m), 1525 (m),1.496 (s), 1477 (m), 1441 (m), 1351 (m), 1232 (m), 1219 (m), 1133 (m),1121 (m), 1104 (m), 1086 (m), 887(m) 825 (m). MS (m/z) 467.8 ([M+H]⁺).

Example 174N(7)-(2-Chlorophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (94 μl, 0.66 mmol), BOP reagent (129 mg, 0.29 mmol) and2-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) gave the titlecompound (88 mg, 66%). M.P.: 110° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):8.54 (s, 1H); 7.59 (d, J=2.1, 1H); 7.42 (dd, J=8.4, 2.4, 1H); 7.34 (d,J=8.4, 1H); 7.28 (dd, J=8.1, 1.6, 1H); 7.15 (td, J=8.1, 1.6, 1H); 7.04(dd, J=8.1, 1.5, 1H); 6.82 (td, J=8.1, 1.5, 1H); 6.55 (br. s, 1H); 3.87(br. t, J=5.1, 1H); 2.58 (br. t, J=5.1, 1H); 2.18 (br. s, 2H); 2.05-1.63(m, 8H); 1.35-1.20 (m, 2H). IR (cm⁻¹, KBr): 3217 (m), 2916 (s), 2847(m), 1678 (s), 1668 (s), 1595 (m), 1498 (s), 1475 (s), 1441 (s), 1361(m), 1232 (m), 1218 (m), 1133 (m), 1106 (m), 1084 (m), 1063 (m), 937(w), 826 (m). MS (m/z) 501.0 ([M+H]⁺).

Example 175N(7)-(2,4-Dichlorophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (82 μl, 0.59 mmol), BOP reagent (123 mg, 0.28 mmol) and2,4-dichlorophenylhydrazine hydrochloride (62 mg, 0.29 mmol) gave thetitle compound (95 mg, 67%). M.P.: 153-156° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.52 (br. s, 1H); 7.59 (d, J=1.8, 1H); 7.42 (dd, J=8.1, 1.8, 1H);7.36-7.24 (m, 2H); 7.12 (dd, J=8.7, 2.4, 1H); 6.97 (d, J=8.7, 1H); 6.48(br. s, 1H); 3.85 (br. s, 1H); 2.57 (br. s, 1H); 2.18 (br. s, 2H);2.00-1.60 (m, 10H). IR (cm⁻¹, KBr): 3307 (m), 2920 (s), 2905 (s); 2848(m), 1682 (s), 1495 (s), 1469 (s), 1388 (m), 1353 (m), 890 (m), 864 (m).MS (m/z): 535.1 ([M+H]⁺).

Example 176N(7)-(2-Bromophenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (82 μl, 0.59 mmol), BOP reagent (123 mg, 0.28 mmol) and2-bromophenylhydrazine hydrochloride (62 mg, 0.29 mmol) yielded thetitle compound (70 mg, 48%). M.P.: 196-199° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.56 (br. s, 1H); 7.59 (d, J=1.8, 1H); 7.45 (br. t, J=8.1, 2H);7.41 (d, J=8.1, 1H); 7.19 (t, J=7.8, 1H); 7.02 (d, J=7.8, 1H); 6.75 (t,J=7.8, 1H); 6.52 (br. s, 1H); 3.87 (br. s, 1H); 2.57 (br. s, 1H); 2.18(br. s, 2H); 2.00-1.60 (m, 8H); 1.30-1.26 (m, 2H). IR (cm⁻¹, KBr): 3216(m), 2915 (s), 2847 (m), 1685 (s), 1595 (m), 1566 (m), 1497 (s),1441(m), 1387 (m), 1352 (m), 1263 (m), 1232 (m), 1218 (m), 1129 (m),1105 (m), 1085 (m), 1062 (m), 1019 (m), 936 (w), 889 (w), 866 (w), 825(m). MS (m/z): 545.1 ([M+H]).

Example 177N(7)-(N′N′-Diphenylamino)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N(74 μl, 0.53 mmol), BOP reagent (123 mg, 0.28 mmol) andN,N-diphenylhydrazine hydrochloride (141 mg, 0.64 mmol) gave the titlecompound (85 mg, 59%). M.P.: 176-180° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):8.96 (s, 1H); 7.57 (d, J=2.1, 1H); 7.40 (dd, J=8.4, 2.1, 1H); 7.35-7.21(m, 9H); 7.01 (br. t, J=8.4, 2H); 3.91 (br. s, 1H), 2.57 (br. s, 1H);2.18 (br. s, 2H); 2.00-1.73 (m, 10H). IR (cm⁻¹, KBr): 3392 (m), 2915(m), 2881 (m), 2845 (m), 1686 (s), 1590 (m), 1493 (s), 1462 (m), 1386(m), 1354 (m), 1340(m), 1311 (m), 1292 (m), 1273(m), 1204 (m), 1150 (m),1102 (m), 1088 (m), 1076 (w), 1028 (w), 866 (w), 822 (w). MS (m/z):543.3 ([M+H]⁺).

Example 178N(7)-(2-Phenylethyl)-5-(2,4-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0ml), Et₃N (41 μl, 0.29 mmol), BOP reagent (123 mg, 0.29 mmol) andphenethylamine (37 μl, 0.29 mmol) gave the title compound (90 mg, 71%).M.P.: 63-66° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d, J=2.1, 1H);7.38 (dd, J=8.4, 2.1, 1H); 7.40-7.18 (m, 6H); 7.02 (t, J=7.2, 1H); 3.97(br. s, 1H); 3.61 (q, J=7.2, 2H); 2.90 (t, J=8.1, 2H); 2.54 (br. s, 1H);2.18 (br. s, 2H); 2.00-1.65 (m, 10H). IR (cm⁻¹, KBr): 3413 (m), 2912(s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233(m), 1219 (m), 1162 (m), 1.103 (m), 1088 (m), 996 (m), 866 (w), 699 (m).MS (m/z): 480.1 ([M+H]⁺).

Example 179N(7)-Benzyl-5-(2′,4′-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

A solution of intermediate 8 (100 mg, 0.27 mmol) in DMF (2 ml) wastreated with BOP reagent (123 mg, 0.28 mmol) and triethylamine (41 μl,0.29 mmol) at room temperature for 15 minutes after which period,benzylamine (32 μl, 0.29 mmol) was added to the mixture and stirred atroom temperature for 1 h. The mixture was poured into water and theprecipitate formed was collected by filteration, dried and purified byflash chromatography to get pure title compound (90 mg, 73%). M.P.:65-66° C. ¹H-NMR (δ ppm, CDCl₃): 7.54 (d, J=2.4, 1H); 7.40-7.18 (m, 5H);4.62 (dd, J=14.7, 6.0, 1H); 4.52 (dd, J=14.7, 6.0, 1H); 4.0 (t, J=5.4,1H); 2.53 (br. s, 1H); 2.18 (br. s, 2H); 1.05-2.10 (m, 10H). IR (cm⁻¹,KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s).

Example 180N(7)-piperidino-5-(2′,4′-dichlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 8 (160 mg, 0.42 mmol), DMF (2 ml),triethylamine (0.06 ml, 0.41 mmol), BOP reagent (187 mg, 0.42 mmol) and1-aminopiperidine (0.05 ml, 0.46 mmol) to give the title compound (106mg, 52%). M.P.: 101-104° C. ¹H-NMR (δ ppm, CDCl₃): 7.58 (br. s, 1H);7.56 (d, J=2.1, 1H); 7.38 (dd, J=8.7, 2.4, 1H); 7.31 (d, J=8.7, 1H);3.96 (br. t, J=5.4, 1H); 2.84 (br. s, 4H); 2.53 (br. s, 1H); 2.17 (br.s, 2H); 1.05-2.10 (m, 14H); 1.72-1.9 (m, 2H). IR (cm⁻¹, KBr): 3413 (m),2914 (s), 2846 (m), 1664 (s), 1534 (s).

Example 181N(7)-(2,4-Dichlorophenylamino)-5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 9 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (45 μl, 0.32 mmol), BOP reagent (136 mg, 0.31 mmol) and2,4-dichlorophenylhydrazine hydrochloride (69 mg, 0.32 mmol) gave thetitle compound (95 mg, 65%). M.P.: 233-240° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.60 (s, 1H); 7.57 (dd, J=7.6, 1.6, 2H); 7.48 (td, J=8.8, 2.4,1H); 7.47-7.37 (m, 2H); 7.29 (d, J=2.4, 1H); 7.11 (dd, J=8.8, 2.4, 1H);6.98 (d, J=8.8, 1H); 3.87 (br. t, J=5.6, 1H); 2.60 (br. t, J=5.6, 1H);2.20 (br. s, 2H); 2.10-1.60 (m, 10H). IR (cm⁻¹, KBr): 3386 (m), 3343(m), 2907 (m), 2870 (m), 2847 (m), 1694 (s), 1497 (m), 1469 (m), 1349(m), 1277 (m), 1259 (m), 1232 (m), 1216 (m), 1087 (m), 1058 (m), 1014(m), 359 (n). MS (m/z): 501.1 ([M+H]⁺).

Example 182N(7)-Benzyl-5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml),triethylamine (46 μl, 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) andbenzylamine (36 μl, 0.32 mmol) to give the title compound (83 mg, 65%).M.P.: 159-161° C. ¹¹H-NMR (δ ppm, CDCl₃): 7.52 (d, J=7.5, 1H); 7.47-7.24(m, 8H); 4.62 (dd, J=15.0, 6.0, 1H); 4.51 (dd, J=15.0, 6.0, 1H); 4.01(br. s, 1H); 2.55 (br. s, 1H); 2.18 (br. s, 2H); 210-1.54 (m, 10H). IR(cm⁻¹, KBr): 3412 (m), 3427(m), 2909 (s), 2845 (m), 1672 (s), 1567 (m),1524 (s), 1498 (s), 1474 (s); 1455(s).

Example 183N(7)-cyclohexyl-5-(2-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml),triethylamine (45 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) andcyclohexylamine (37 0.32 mmol) to give the title compound (95 mg, 77%).M.P.: 218-220° C. ¹H-NMR (δ ppm, CDCl₃): 7.55-7.52 (m, 1H); 7.42-7.35(m, 3H); 6.80 (br. d, J=8.1, 1H); 4.00 (br. t, J=5.4, 1H); 3.97-3.83 (m,1H); 2.54 (br. s, 1H); 2.17 (br. s, 2H); 1.99 (br. s, 6H); 1.92-1.52 (m,8H); 1.55-1.05 (m, 6H). IR (cm⁻¹, KBr) 3409 (m), 2921(s), 2904(s),2849(m), 1667(s), 1567(m), 1527(s), 1494(s), 1479(s).

Example 184N(7)-piperidino-5-(2′-chlorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 ml),triethylamine (45 μl, 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) and1-aminopiperidine (35 μl, 0.32 mmol) to give the title compound (90 mg,72%). M.P.: 251-254° C. ¹H-NMR (δ ppm, CDCl₃): 7.62 (br. s, 1H); 7.54(d, J=8.7, 1H); 7.53-7.35 (m, 3H); 3.98 (br. s, 1H); 2.84 (t, J=4.8,4H); 2.54 (br. s, 1H), 2.17 (br. s, 2H); 1.98 (t, J=12.6, 4H); 1.93-1.50(m, 10H); 1.44-1.34 (m, 2H). IR (cm⁻¹, KBr): 3314 (m), 2905 (s), 2844(m), 2804 (m), 1686 (s), 1567 (m), 1525 (s), 1492 (s), 1480 (s).

Example 185N7-(2-Chlorobenzyl)-5-(5-chloro-2-pyridyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 10 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and2-chloro-benzylamine (31 mg, 0.29 mmol) furnished the title compound (64mg, 49%). M.P.: 187-189° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.81 (t,J=6.3, 1H), 8.60 (d, J=2.6, 1H); 8.19 (dd, J=8.6, 2.6, 1H); 7.96 (d,8.6, 1H); 7.46-7:42 (m, 1H); 7.38-7.27 (m, 3H); 4.48 (d, J=6.0, 2H);4.04 (s, 1H); 3.78 (m, 1H); 2.14 (br. s, 2H); 1.95-1.68 (m; 10H).

Example 186N(7)-Benzyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 10:1 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 ml),triethylamine (0.06 ml, 0.43 mmol), BOP reagent (190 mg, 0.43 mmol) andbenzylamine (0.05 ml, 0.43 mmol) to give the title compound (96 mg,69%). M.P.: 218-219° C. ¹H-NMR (δ ppm, DMSO-d₆): 12.70 (br. s, 1H); 8.44(br. s, 1H); 7.30 (m, 5H); 4.36 (br. s, 2H); 3.71 (br. s, 1H); 2.97 (br.s, 1H); 2.10 (br. s, 2H); 1.9.1 (br. s, 4H); 1.77 (br. s, 2H); 1.65 (t,J=13.2, 10H). IR (cm⁻¹, KBr): 3434 (s), 2924 (s), 2854 (m), 1634 (m).

Example 187N(7)-Piperidine-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

A solution of intermediate 11 (160 mg, 0.68 mmol) in DMF (3 ml) wastreated at room temperature with EPCI (198 mg, 1.02 mmol), HOBt (93 mg,0.68 mmol), triethylamine (0.19 ml, 1.36 mmol), DMAP (8 mg) and1-aminopiperidine (0.081 ml, 0.68 mmol) for 16 h. Dilution of themixture with water, extraction into ethyl acetate, drying over Na₂SO₄,evaporation and purification by flash chromatography gave the titlecompound (134 mg, 63%). M.P.: 295-297° C. ¹H-NMR (δ ppm, DMSO-d₆): 12.61(br. s, 1H); 8.61 (br. s, 1H); 3.65 (br. s, 1H); 3.00 (br. s, 1H); 2.10(br. s, 2H); 1.99-1.51 (m, 1H); 1.33 (br. s, 2H). IR (cm⁻¹, KBr): 3314(m), 3199(s), 3155 (m); 3085 (m), 3003 (m), 2907 (s), 2843 (s), 2805(m),1653 (s), 1590 (m), 1543 (m), 1509 (m).

Example 1886,7-Diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-5-diene-5-yl-piperidinomethanone

The title compound was synthesized as per the procedure described forexample 101 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 ml),triethylamine (0.06 mg, 0.43 mmol), BOP reagent (190 mg, 0.43 mmol) andpiperidine (43 μl, 0.43 mmol) to give the title compound (84 mg, 66%).M.P.: 263-264° C. ¹H-NMR (δ ppm, CDCl₃): 3.57 (br. s, 4H); 3.05 (br. s,1H); 2.92 (br. s, 1H); 2.17 (br. s, 2H); 2.10-1.50 (m, 16H). IR (cm⁻¹,KBr): 3436 (m), 3198(s), 3155 (m); 2924 (s), 2905 (s), 2888 (s), 1607(s), 1598 (s), 1583 (s).

Example 189aN(7)-Piperidino-6-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

A 0.27 M solution of KOH in ethanol-water 4:3 (3.5 ml) was added to asolution of intermediate 12a (123 mg, 0.45 mmol) and refluxed for 3 h.After concentration of the mixture to approx. half of its initialvolume, it was acidified with aq. 1N HCl and the precipitated solid wasfiltered, dried and dissolved in DMF (3 ml). The solution was treatedwith DMAP (5 mg), EPCI (100 mg, 0.5 mmol), HOBt (47 mg, 0.35 mmol),1-aminopiperidine (39 mg, 0.35 mmol) and triethylamine (0.08 ml, 0.56mmol) at room temperature for 15 h. Dilution of the mixture with water,extraction into ethyl acetate, drying over Na₂SO₄ and purification byflash chromatography gave the title compound (48 mg, 33%). M.P.: 188.9°C. ¹H-NMR (δ ppm, DMSO-d₆): 6.27 (br. s, 1H); 3.88 (s, 3H); 3.06-2.92(m, 2H); 2.87 (t, J=5.4, 4H); 2.15 (br. s, 2H); 2.10-1.91 (m, 4H);1.90-1.70 (10H); 1.55-1.40 (m, 2H). IR (cm⁻¹, KBr): 3440 (br., m); 3227(m), 2918(s), 2844 (s), 1636 (s), 1557 (m), 1532 (m).

Example 189bN(7)-Piperidino-5-methyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized as per the procedure described forexample 189a using intermediate 12b (173 mg, 0.63 mmol), ethanol (2 ml),0.27 M solution of KOH in ethanol-water 4:3 (3.5 ml), DMF (3 ml), DMAP(8 mg), EPCI (167 mg, 0.87 mmol), HOBt (78 mg, 0.58 mmol),1-aminopiperidine (58 mg, 0.35 mmol) and triethylamine (0.13 ml, 0.93mmol) to give the title compound in pure form (148 mg, 72%). M.P.:218.7° C. ¹H-NMR (δ ppm, DMSO-d₆): 7.56 (br. s, 1H); 3.89 (t, J=5.4,1H); 3.74 (s, 3H); 2.97 (t, J=5.1, 1H); 2.85 (t, J=5.1, 4H); 2.162.00-1.88 (m, 4H); 1.90-1.66 (10H); 1.47-1.36 (m, 2H).

Example 190aN(7)-(1-Methyl-1-phenylethyl)-6-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4,7-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 189a. Intermediate 13a (100 mg, 0.33 mmol), DMF(1.0 ml), Et₃N (52 μl, 0.36 mmol), BOP reagent (160 mg, 0.36 mmol) andα,α-dimethylbenzylamine (53 mg, 0.39 mmol) furnished the title compound(100 mg, 72%). M.P.: 66-69° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.46-7.40(m, 2H); 7.58 (t, J=7.2, 2H); 7.30-7.20 (m, 2H); 5.83 (br. s, 1H); 4.14(t, J=7.8, 2H); 3.11 (br. t, J=5.2, 1H); 3.03 (br. t, J=5.2, 1H); 2.15(br. s, 1H); 2.08-1.94 (m, 4H); 1.79 (s, 6H); 1.80-1.70 (m, 6H);1.32-1.20 (m, 4H); 0.87 (t, J=7.5, 3H).

Example 190bN(7)-(1-Methyl-1-phenylethyl)-5-pentyl-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8)-6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 189b. Intermediate 13b (100 mg, 0.33 mmol), DMF(1.0 ml), Et₃N (52 μl, 0.36 mmol), BOP reagent (160 mg, 0.36 mmol) andα,α-dimethylbenzylamine (53 mg, 0.39 mmol) furnished the title compound(95 mg, 68%). M.P.: 99-102° C. ¹H-NMR. δ ppm, CDCl₃, 300 MHz): 7.50-7.44(m, 2H); 7.32 (t, J=7.2, 2H); 7.24-7.16 (m, 2H); 3.97 (t, J=7.5, 2H);3.82 (br. s, 1H); 2.94 (br. s, 1H); 2.13 (br. s, 2H); 2.00-1.84 (m, 4H);1.78 (s, 6H); 1.80-1.68 (m, 6H); 1.40-1.24 (m, 4H); 0.91 (t, J=7.2, 3H).

Example 191N(7)-[(1R)-2-Hydroxy-1-phenylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

To a solution of example 154 (290 mg, 0662 mmol) in THF (3 ml) was addedLiBH₄ (32 mg, 1.52 mmol) and the mixture was refluxed overnight. Afterevaporation of the solvent, the oily residue was diluted with water andacidified with 1N HCl and extracted with ethyl, acetate and the combinedorganic layers were washed with brine and dried over Na₂SO₄. PC (3:7AcOEt/petroleum ether) gave the title compound (150 mg, 61%). M.P.:161-162° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.24 (d, J=7.5, 1H);7.76-7.58 (m, 2H); 7.38-7.20 (m, 6H); 5.02-4.92 (m, 2H), 3.77 (br. s,1H); 3.70-3.64 (m, 2H); 2.62 (br. s, 1H); 2.12 (br. s, 2H); 1.98-1.68(m, 10H). IR (cm⁻¹, KBr): 3403 (m), 3007 (w), 2916 (s), 2848 (m), 1656(s), 1612 (w), 1519 (s), 1483 (m), 1443 (m), 1368 (m), 1.353 (m), 1273(m), 1225 (n) 1144 (m), 1082 (m), 966 (m), 851 (m). MS (m/z): 452.17(M+H⁺).

Example 192N(7)-[(1S)-2-Hydroxy-1-phenylethyl]-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 191. The product of example 155 (400 mg, 0.81mmol), THF (5 ml) and LiBH₄ (35 mg, 1.62 mmol) furnished the titlecompound (130 mg, 34%). M.P.: 158-159° C. ¹H-NMR (δ ppm, DMSO-d₆, 300MHz): 8.24 (d, J=8.1, 1H); 7.71 (q, 8.4, 1H); 7.61 (t, J=8.4, 1H);7.38-7.20 (m, 6H); 5.00-4.94 (m, 2H), 3.78 (br. s, 1H); 3.72-3.64 (m,2H); 2.62 (br. s, 1H); 2.11 (br. s, 2H); 2.00-1.65 (m, 10H). MS (m/z):452.17 (M+H⁺).

Example 201N(3)-Piperidino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0ml), Et₃N (66 μl, 0.47 mmol), BOP reagent (191 mg, 0.43 mmol) and1-aminopiperidine (42 μl, 0.39 mmol) gave the title compound (45 mg,34%). M.P.: 144° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.68 (d, J=7.8, 2H);7.68 (br. s, 1H); 7.48 (t, J=7.8, 1H); 7.32 (t, J=7.8, 1H); 3.75 (br. s,1H); 3.70 (br. s, 1H); 2.91 (br. s, 4H); 2.11 (br. d, J=8.1, 1H); 1.98(br. d, J=9.3, 2H); 1.80-1.50 (m, 5H); 1.45 (br. s, 2H); 1.24 (br. d,J=8.1, 2H). IR (KBr, cm⁻¹): 3302 (m), 2987 (m), 2940 (s), 2856 (m), 2790(m), 1686 (s), 1597 (m), 1537 (s), 1513 (s), 1489 (s), 1444 (m), 1339(m), 1270 (m), 1225 (m), 1140 (m), 1127 (m), 1075 (w), 1036(w), 918 (m),893 (m), 832 (w). MS (m/z): 337.1 ([M+H]⁺).

Example 202N(3)-Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0ml), Et₃N (66 μl, 0.48 mmol), BOP reagent (191 mg, 0.43 mmol) andcyclohexylamine (45 μl, 0.39 mmol) yielded the title compound (99 mg,75%). M.P.: 107° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.68 (d, J=8.1, 2H);7.48 (t, J=8.1, 2H); 7.33 (t, J=7.8, 1H); 6.80 (br. d, J=8.4, 1H);3.97-3.95 (m, 1H); 3.75 (br. s, 1H); 3.69 (br. s, 1H); 2.12 (hr. d,J=8.7, 1H); 2.11-1.90 (m, 4H); 1.79-1.65 (m, 4H); 1.48-1.15 (m, 7H). IR(KBr, cm⁻¹): 3327 (m), 2936 (m), 2856 (m), 1655 (s), 1595 (m), 1549 (s),1508 (s), 1490 (s), 1462 (s), 1448 (m), 1352 (s), 1272 (m), 1249 (m),1226 (m), 1164 (m), 1140 (m), 1121 (m). MS (m/z): 336.1 ([M+H]⁺).

Example 203N(3)-Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0ml), Et₃N (66 μl, 0.48 mmol), BOP reagent (191 mg, 0.43 mmol) and benzylamine (45 0.39 mmol) gave the title compound (87 mg, 65%). M.P.: 115° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66 (d, J=7.5, 2H); 7.47 (t, J=7.8,2H); 7.40-7.26 (m, 7H); 4.64 (d, J=5.4, MO, 3.78 (br. s, 1H); 3.71 (br.s, 1H); 2.15 (br. d, J=8.4, 1H); 2.00 (br. d, J=8.7, 2H); 1.73 (br. d,J=8.4, 1H); 1.30-1.14 (m, 2H). IR (KBr, cm⁻¹): 3376 (m), 2995 (m), 2966(m), 2948 (m), 2863 (m), 1652 (s), 1595 (s), 1552 (s), 1354 (s), 1277(m), 1256 (m), 1235 (s), 1157 (m), 1122 (m), 1070 (m), 988 (m). MS(m/z): 344.1 ([M+H]⁺).

Example 204N(3)-Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0ml), Et₃N (66 μl, 0.48 mmol), BOP reagent (191 mg, 0.43 mmol) andphenylhydrazine (38 μl, 0.39 mmol) gave the title compound (111 mg,82%). M.P.: 189° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.59 (br. s, 1H);7.71 (d, J=8.1, 2H); 7.50 (t, J=8.1, 2H); 7.35 (t, J=8.1, 1H); 7.24 (t,J=7.8, 2H); 6.96 (d, J=7.8, 2H); 6.90 (t, J=7.8, 1H); 3.73 (br. s, 2H);2.14 (br. d, J=8.7, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J=8.4, 1H);1.31-1.14 (m, 2H). IR (KBr, cm⁻¹): 3413 (m), 3393 (m), 3273 (s), 2970(m), 2955 (m), 2868 (w), 1682 (s), 1599 (m), 1541 (m), 1506 (s), 1493(s), 1476 (s), 1458 (s), 1349 (m), 1273 (m), 1226 (m), 1157 (m), 1132(m), 1085 (m), 1066 (m), 895 (m). MS (m/z): 345.1 ([M+H]⁺).

Example 205N(3)-Piperidino-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (169 mg, 0.38 mmol) and 1aminopiperidine (38 μl, 0.35 mmol) gave the title compound (100 mg,78%). M.P.: 232° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.60-7.47 (m, 3H);7.42-7.35 (m, 2H); 3.76 (br. s, 1H); 3.37 (br. s, 1H); 2.80 (br. s, 4H);2.13 (br. d, 9.3, 1H); 2.11-1.86 (m, 2H); 1.75-1.62 (m, 5H); 1.42-1.18(m, 4H), IR (KBr, cm⁻¹): 3314 (w), 29.99 (w), 2938 (s), 2867 (w), 2781(m), 1682 (s), 1540 (s), 1511 (s), 1484 (s), 1450 (m), 1342 (m), 1276(w), 1257 (w), 1227 (m), 1123 (m), 1083 (m), 1035 (m), 987 (m), 893 (w).MS (m/z): 371.1 ([M+H]⁺).

Example 206N(3)-Cyclohexyl-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 15 (100 mg, 035 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (169 mg, 0.38 mmol) andcyclohexyl amine (40 0.39 mmol) yielded the title compound (92 mg, 72%).M.P.: 171° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.45 (m, 2H);7.45-7.35 (m, 2H); 6.73 (br. d, J=7.2, 1H); 3.95-3.82 (m, 1H); 3.77 (br.s, 1H); 3.37 (br. s, 1H); 2.13 (br. d, J=9.3, 1H); 2.11-1.86 (m, 4H);1.70-1.66 (m, 4H); 1.42-1.18 (m, 7H). IR (KBr, cm⁻¹): 3407 (m), 3393(m), 2996 (m), 2934 (s), 2850 (s), 1662 (s), 1549 (s), 1513 (s), 1506(s), 1483 (s), 1447 (s), 1342 (s), 1223 (s), 1.125 (s), 1085 (m), 965(m), 950 (m). MS (m/z): 370.1 ([M+H]⁺).

Example 207N(3)-Benzyl-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (169 mg, 0.38 mmol) and benzylamine (37 μl, 0.34 mmol) yielded the title compound (60 mg, 46%). ¹H-NMR(δ ppm, CDCl₃, 300 MHz): 7.55-7.15 (m, 10H); 4.60 (br. s, 2H); 3.79 (br.s, 1H); 3.38 (br. s, 1H); 2.16 (hr. d, J=7.8, 1H); 1.99-1.88 (m, 2H);1.70 (d, J=8.7, 1H); 1.31-1.20 (m, 2H). IR (Neat, cm⁻¹): 3414 (m), 2994(m), 2968 (m), 2949 (m), 1664 (s), 1550 (s), 1513 (s), 1485 (s), 1455(s), 1347 (m), 1275 (m), 1251 (m), 1.235 (m), 1161 (m), 1141 (m), 1121(m). MS (m/z): 378.1 ([M+H]⁺).

Example 208N(3)-Phenylamino-1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 15 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (169 mg, 0.38 mmol) and phenylhydrazine (34 μl, 0.34 mmol) gave the title compound (105 mg, 80%).M.P.: 205° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.51 (s, 1H); 7.60-7.51(m, 2H); 7.52-7.40 (m, 2H); 7.23 (t, J=7.8, 2H); 6.95 (d, J=7.8, 2H);6.90 (t, J=7.5, 1H); 3.74 (br. s, 1H); 3.41 (br. s, 1H); 2.15 (br. d,J=8.7, 1H); 2.00-1.85 (m, 2H); 1.70 (br. d, J=8.7, 1H); 1.32-1.20 (m,2H). IR (KBr, cm⁻¹): 3283 (s), 2993 (m), 2955 (m), 1675 (s), 1591 (m),1603 (m), 1542 (m), 1513 (s),1497 (s),1439 (m), 1348 (m), 1281 (m), 1238(m), 1137 (m), 1123 (m), 1082 (m),1062 (m), 889 (m). MS (m/z): 379.0([M+H]⁺).

Example 209N(3)-Piperidino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (1.52 mg, 0.35 mmol) and1-amino piperidine (37 μl, 0.35 mmol) yielded the title compound (68 mg,53%). MP: 78-81° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63 (d, J=8.7, 2H);7.44 (d, J=8.7, 2H); 3.75 (s, 1H); 3.67 (s, 1H); 2.91 (br. s, 4H); 2.11(br. d, J=8.7, 1H); 2.00 (br. d, J=9.6, 2H); 1.80-1.65 (m, 5H): 1.45 (m,2H); 1.20 (m, 2H). IR (KBr, cm⁻¹): 3408 (m), 2931 (m), 2871 (m), 2779(m), 1692 (s), 1540 (m), 1506 (s), 1489 (s), 1347 (m), 1268 (m), 1227(m), 1085 (m). MS (m/z): 371.2 ([M+H]⁺).

Example 2101-(4-Chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazol-3-ylpiperidino methanone

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (0.100 mg, 0.35 mmol), DMF(1.0 ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (160 mg, 0.36 mmol) andpiperidine (38 μl, 0.38 mmol) furnished the title compound (80 mg, 65%).M.P.: 96-98° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63 (d, J=8.7, 2H);7.41 (d, J=8.7, 2H); 3.92-3.75 (m, 4H), 3.69 (br. s, 1H), 3.57 (s, 1H),2.13 (d, J=6.9, 1H), 1.97 (d, J=9.0, 2H), 1.80-1.60 (m, 7H), 1.24 (d,J=8.7, 2H). IR (cm⁻¹, KBr): 2932 (s), 2861 (m), 1613 (s), 1503 (s), 1467(m), 1422 (m), 137.1 (m), 1352 (m), 1271 (m), 1246 (m), 1156 (w), 1132(m), 1088 (m), 825 (m). MS (m/z): 356.0 ([M+H]⁺).

Example 211N(3)-Cyclohexyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) andcyclohexylamine (39 μl, 0.35 mmol) to give the title compound (98 mg,77%). M.P.: 155-158° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.64 (d, J=8.7,2H); 7.43 (d, J=8.7, 2H); 6.76 (br. d, J=8.7, 1H); 4.02-3.87 (m, 1H);3.75 (s, 1H); 3.67 (s, 1H); 2.12 (br. d, J=8.1, 1H); 2.10-1.90 (m, 4H);1.80-1.57 (m, 4H); 1.48-1.18 (m, 7H) IR (KBr, cm⁻¹): 3411 (m), 2926 (s),2848 (m), 1666 (s), 1598 (w), 1545 (s), 1505 (s), 1486 (s), 1349 (m),1248 (w), 1223 (m), 1159 (m), 1122 (m), 1086 (m), 829 (m), 506 (m). MS(m/z): 370.3 ([M+H]⁺).

Example 212N(3)-Cyclopentyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (160 mg, 0.36 mmol) andcyclopentylamine (38 μl, 0.38 mmol) yielded the title compound (95 mg,77%). M.P.: 176-178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63 (d, J=8.7,2H); 7.43 (d, J=8.7, 2H); 6.81 (d, J=7.5, 1H); 4.38 (sextet, J=7.5, 1H);3.76 (s, 1H), 3.66 (s, 1H), 2.20-1.90 (d, J=8.7, 5H); 1.8-1.40 (m, 7H);1.28-1.20 (m, 2H). IR (cm⁻¹, KBr): 3288 (m), 2964 (s), 2868 (m), 1643(s), 1552 (s), 1505 (s), 1489 (s), 1442 (m), 1406 (m), 1364 (m), 1347(m), 1275 (m), 1252 (m), 1243 (m), 1158 (m), 1129 (m), 1089 (m), 1008(m), 836 (m). MS (m/z): 356.0 ([M+H]⁺).

Example 213N(3)-[(N-Cyclohexyl-N-methyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-ethano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (300 mg, 1.039 mmol), DMF (3ml), Et₃N (173 μl, 1.25 mmol), BOP reagent (459 mg, 1.039 mmol) andN-methyl-N-cyclohexylhydrazine (132 mg, 1.04 mmol) yielded the titlecompound (285 mg, 69%). MP: 62° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63(d, J=8.7, 2H); 7.62 (br. s, 1H); 7.44 (d, J=9.0, 2H); 3.77 (s, 1H);3.67 (s, 1H); 2.73 (br. s, 3H); 2.13 (br. d, J=8.7, 1H); 2.10-1.90 (m,4H); 1.72 (br. d, J=8.7, 1H); 1.80-1.15 (m, 11H). IR (KBr, cm⁻¹) 3258(m), 2930 (s), 2854 (s), 1678 (s), 1596 (m), 1544 (s), 1501 (s), 1447(s), 1350 (s), 1274 (m), 1233 (m), 1159 (m), 1121 (m), 1090 (s), 1051(m), 1006 (m), 915 (m), 866 (m), 831 (s). MS (m/z): 399.1 ([M+H]⁺).

Example 214N(3)-Phenyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) andaniline (31 μl, 0.35 mmol) gave the title compound (80 mg, 64%). M.P.:137-140° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.70 (s, 1H); 7.69 (t,J=9.9, 4H); 7.48 (d, J=9.0, 2H); 7.36 (t, J=7.9, 2H); 7.12 (t, J=7.4,1H); 3.80 (s, 1H); 3.71 (s, 1H); 2.17 (br. d, J=9.0, 1H); 2.10-1.95 (m,2H); 1.76 (br. d, J=-9.0, 1H); 1.38-1.19 (m, 2H). IR (KBr, cm⁻¹): 3283(m), 2933 (w), 2865 (w), 1663 (s), 1597 (s), 1542 (s), 1500 (s), 1433(m), 1350 (m), 1240 (m), 1089 (m), 833 (m), 759 (m), 507 (w). MS (m/z):364.3 ([M+H]⁺).

Example 215N(3)-(3-Chlorophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (54 μl, 0.38 mmol), BOP reagent (162 mg, 0.37 mmol) and3-chloroaniline (49 mg, 0.38 mmol) furnished the title compound (110 mg,78%). M.P.: 158-161° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.71 (br. s,1H); 7.87 (t, J=1.8, 1H); 7.67 (d, J=8.7, 2H); 7.54 (br. d, J=8.1, 1H);7.48 (d, J=8.7, 2H); 7.28 (t, J=8.1, 1H); 7.09 (br. d, J=8.1, 1H); 3.80(br. s, 1H); 3.71 (br. s, 1H); 2.17 (br. d, J=9.0, 1H); 2.12-1.97 (m,2H); 1.76 (d, J=8.7, 1H); 1.32-1.20 (m, 2H). IR (cm⁻¹, KBr): 3295 (s),3187 (w), 3059 (w), 2987 (m), 2960 (m), 2984 (m), 2866 (m), 1677 (s),1593 (s), 1551 (m), 1497 (s), 1484 (s), 1410 (m), 1400 (m), 1355 (m),1308 (m), 1297 (w), 1234 (m), 1220 (m), 1157 (w), 1141 (m), 1091 (m),1077 (w), 1048 (w), 1008 (m), 997 (m) 875 (m), 825 (m). MS (m/z): 398.2([M+H]⁺).

Example 216N(3)-(4-Chlorophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (160 mg, 0.36 mmol) and4-chloroaniline (49 mg, 0.39 mmol) yielded the title compound (80 mg,58%). M.P.: 182-184° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.69 (s, 1H);7.67 (d, J=8.7, 4H); 7.47 (d, J=8.7, 2H); 7.32 (d, J=8.7, 2H); 3.80 (s,1H), 3.71 (s, 1H), 2.16 (d, J=8.7, 1H); 2.03 (d, J=7.2, 2H); 1.76 (d,J=8.7, 1H); 1.26 (d, J=7.5, 2H). IR (cm⁻¹, KBr): 3306 (m), 2989 (w),2971 (w), 2945 (m), 2868 (w), 1673 (s), 1660 (s), 1594 (s), 1545 (s),1498 (s), 1407 (s), 1397 (m), 1310 (m), 1284 (m), 1240 (m), 1089 (s),1008 (m), 828 (s). MS (m/z): 398.0 ([M+H]⁺).

Example 217N(3)-(3-Bromophenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (160 mg, 0.36 mmol) and3-bromoaniline (42 μl, 0.38 mmol) furnished the title compound (90 mg,59%). M.P.: 176-178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.69 (s, 1H);8.00 (d, J=2.1, 1H); 7.66 (d, J=7.5, 2H); 7.61 (br. d, J=7.5, 1H); 7.47(d, J=7.5, 2H); 7.25-7.17 (m, 2H); 3.80 (s, 1H), 3.71 (s, 1H), 2.16 (d,J=8.7, 1H); 2.03 (d, J=−7.8, 2H); 1.76 (d, J=8.7, 1H); 1.26 (d, J=7.2,2H). IR (cm⁻¹, KBr): 3292 (m), 2987 (w), 2865 (w), 1675 (s), 1587 (s),1497 (s), 1481 (s), 1409 (m), 1397 (m), 1355 (m), 1306 (m), 1233 (m),1157 (m), 1091 (m), 874 (w), 825.

Example 218N(3)-(2-Methoxyphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (153 mg, 0.35 mmol) ando-anisidine (39 μl, 0.35 mmol) gave the title compound (100 mg, 74%).M.P.: 149-151° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 9.32 (br. s, 1H); 8.54(dd, J=8.1, 2.1, 1H); 7.69 (d, J=9.0, 2H); 7.47 (d. J=9.0, 2H);7.1.0-7.02 (m, 2H); 6.92 (dd, J=7.8, 1.5, 1H); 3.94 (s, 3H); 3.81 (br.s, 1H); 3.71 (br. s, 1H); 2.17 (d, J=7.8, 1H); 2.02 (br. d, J=8.4, 2H);1.76 (d, J=8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm⁻¹): 3380 (m), 2873(w), 1684 (s), 1601 (m), 1541 (s), 1499 (s), 1479 (s), 1461 (s), 1349(m), 1247 (m), 1219 (m), 1118 (m), 1089 (m), 1044(M), 1027 (m), 838 (m).MS (m/z): 394.2 ([M+H]⁺).

Example 219N(3)-(4-tert-Butylphenyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (160 mg, 0.36 mmol) and4-tert-butylaniline (62 0.38 mmol) yielded the title compound (100 mg,69%). M.P.: 76-78° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.65 (s, 1H); 7.67(d, J=8.7, 2H); 7.63 (d, J=8.7, 2H); 7.47 (d, J=8.7, 2H); 7.37 (d,J=9.0, 2H); 3.81 (s, 1H), 3.70 (s, 1H), 2.16 (d, J=9.0, 1H); 2.02 (d,J=8.4, 2H); 1.75 (d, J=9.0, 1H); 1.33 (s, 9H); 1.40-1.20 (m, 2H). IR(cm⁻¹, KBr): 2962 (m), 2868 (m), 1685 (s), 1589 (m), 1537 (s), 1519 (s),1492 (s), 1407 (m), 1349 (m), 1243 (m), 1219 (m), 1134 (w), 1121 (w),1091 (s), 1047 (w), 1009 (w), 830 (s). MS (m/z): 420.1 ([M+H]⁺).

Example 220N(3)-Benzyl-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) andbenzylamine (37 μl, 0.35 mmol) gave the title compound (67 mg, 51%) MP:112-115° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (d, J=9.0, 2H);7.45-7.20 (m, 8H); 4.63 (br. d, J=5.7, 2H); 3.78 (s, 1H); 3.68 (s, 1H);2.14 (br. d, J=8.5, 1H); 2.05-1.90 (m, 2H); 1.73 (br. d, J=8.5, 1H);1.35-1.17 (m, 2H). IR (KBr, cm⁻¹): 3318 (m), 2995 (m), 2930 (m), 1652(s), 1548 (s), 1501 (s), 1352 (m), 1275 (m), 1239 (m), 1120 (m), 1089(m), 830 (m), 701(w), 508 (w). MS (m/z): 378.3 ([M+H]⁺).

Example 221 N(3)-(2-Chlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and2-chlorobenzylamine (41 μl, 0.35 mmol) gave the title compound (91 mg,64%). M.P.: 119-122° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.63 (d, J=9.0,2H); 7.43 (d, j=9.0, 2H); 7.51-7.20 (m, 5H); 4.72 (d, J=6.3, 2H); 3.76(s, 1H); 3.67 (s, 1H); 2.12 (br d, J=8.6, 1H); 2.10-1.90 (m, 2H); 1.73(hr. d, J=8.6, 1H); 1.35-1.19 (m, 2H). IR (KBr, cm⁻¹): 3319 (m), 2955(m), 2868 (m), 1651 (s), 1595 (m), 1547 (m), 1490 (s), 1442 (m), 1352(m), 1277 (m), 1237 (m), 1160 (m), 1123 (m), 1091 (m), 1007 (m), 993(m), 835 (m). MS (m/z): 412.0 ([M+H]⁺).

Example 222N(3)-(4-Chlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and4-chlorobenzylamine (42 μl, 0.35 mmol) yielded the title compound (104mg, 73%). M.P.: 157-160° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (d,J=8.7, 2H); 7.42 (d, J=8.7, 2H); 7.31 (s, 4H); 7.23 (br. s, 1H); 4.59(d, J=5.6, 2H); 3.77 (s, 1H); 3.68 (s, 1H); 2.14 (br. d, J=8.6, 1H);2.10-1.90 (m, 2H); 1.73 (hr. d, J=8.6, 1H); 1.35-1.18 (m, 2H). IR (KBr,cm⁻¹): 3324 (m), 2979 (m), 2951 (m), 287.5 (m), 1649 (s), 1560 (s), 1513(s), 1444 (m), 1406 (m), 1354 (m), 1244 (m), 1160 (m), 1144 (m), 1092(s), 1007 (m), 980 (m), 946 (m), 835 (s), 626 (m), 509 (w). MS (m/z):412.0 ([M+H]⁺).

Example 223N(3)-(2,4-Dichlorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and2,4-dichlorobenzylamine (46 μl, 0.35 mmol) gave the title compound (104mg, 67%). MP: 108-111° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.62 (d,J=8.7, 2H); 7.50-7.30 (m, 4H); 7.34 (br. s, 1H); 4.70 (d, J=6.3, 2H);3.75 (s, 1H); 3.68 (s, 1H); 2.13 (br. d, J=9.0, 1H); 2.10-1.90 (m, 2H);1.73 (br d, J=9.0, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm⁻¹): 3294 (m),2988 (w), 2949 (w), 1652 (s), 1554 (m), 1502 (s), 1491 (s), 1356 (m),1.252 (m), 1092 (m), 831 (s). MS (m/z): 447.9 ([M+H]⁺).

Example 224N(3)-(2-Bromobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (0.10 ml, 0.69 mmol), BOP reagent (0.153 g, 0.35 mmol) and2-bromobenzylamine hydrochloride (77 mg, 0.35 mmol) to give the titlecompound (105 mg, 67%). M.P.: 141-142° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.60-7.50 (m, 3H); 7.50-7.22 (m, 5H); 7.14 (td, J=7.8, 1.5, 1H);4.70 (d, J=6.3, 2H); 3.80 (s, 1H); 3.70 (s, 1H); 2.14 (br. d, J=8.7,1H); 2.10-1.80 (m, 2H); 1.70 (br. d, J=8.7, 1H); 1.35-1.15 (m, 2H). IR(KBr, cm⁻¹): 3322 (m), 2954 (w), 2867 (w), 1651 (s), 1548 (m), 1503 (s),1350 (m), 1277 (w), 1236 (w), 1091 (s), 835 (m). MS (m/z): 458.1([M+H]⁺).

Example 225N(3)-(4-Bromobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (0.096 ml, 0.69 mmol), BOP reagent (0.153 g, 0.35 mmol) and4-bromobenzylamine hydrochloride (77 mg, 0.35 mmol) furnished the titlecompound (118 mg, 64%). M.P.; 181-183° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.60 (d, J=6.9, 2H); 7.50-7.40 (m, 4H); 7.30-7.20 (m, 2H); 4.60(br. d, J=5.1, 2H); 3.80 (s, 1H); 3.70 (s, 1H); 2.14 (br. d, J=9.0, 1H);2.07-1.92 (m, 2H); 1.70 (br. d, J=9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr,cm⁻¹): 3325 (m), 2979 (m), 2950 (m), 1648 (s), 1558 (m), 1505 (s), 1489(s), 1353 (m), 1253 (m), 1092 (m), 835 (s). MS (m/z): 458.0 ([M+H]⁺).

Example 226N(3)-(4-Fluorobenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 1.6 (100 mg, 0.35 mmol), DMF(1.0 ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and4-fluorobenzylamine (39 μl, 0.35 mmol) yielded the title compound (95mg, 69%). M.P.: 104-107° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (d,J=9.0, 2H); 7.42 (d, J=9.0, 2H); 7.35 (dd, J=8.6, 5.7, 2H); 7.21 (br. s,1H); 7.02 (t, J=8.6, 2H); 4.59 (d, J=6.0, 2H); 3.77 (s, 1H); 3.68 (s,1H); 2.13 (br. d, J=8.7, 1); 2.10-1.90 (m, 2H); 1.73 (br. d, J=9.0, 1H);1.40-1.18 (m, 2H). IR (KBr, cm⁻¹): 3314 (m), 2968 (m), 2940 (m), 2872(w), 1647 (s), 1554 (m), 1509 (s), 1357 (m), 1218 (m), 1091 (s), 832(s), 626 (w), 564 (w). MS (m/z): 396.1 ([M+H]⁺).

Example 227N(3)-(4-Trifluoromethylbenzyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and4-trifluoromethylbenzylamine (49 μl, 0.35 mmol) to furnished titlecompound (104 mg, 68%). M. P.: 165-168° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.67-7.57 (m, 4H); 7.48 (d, J=8.7, 2H); 7.43 (d, J=8.7, 2H); 7.30(br. t, J=6.0, 1H); 4.68 (d, J=5.7, 2H); 3.77 (s, 1H); 3.69 (s, 1H);2.13 (br. d, J=8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (br. d, J=7.2, 1H);1.30-1.18 (m, 2H). IR (KBr, cm⁻¹): 3323 (m), 2969 (m), 2953 (m), 2874(w), 1648 (s), 1557 (m), 1504 (s), 1439 (m), 1406 (m), 1417 (m), 1325(s), 1282 (m), 1245 (m), 1161 (s), 1122 (s), 1110 (s), 1092 (s), 1064(s), 847 (m), 832 (m), 625 (w), 509 (w). MS (m/z): 446.0 ([M+H]⁺).

Example 228N(3)-Phenylamino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) andphenylhydrazine (34 μl, 0.35 mmol) gave the title compound (92 mg, 70%).MP: 138-141° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.55 (s, 1H); 7.67 (d,J=8.5, 2H); 7.46 (d, J=8.5, 2H); 7.24 (t, J=7.5, 2H); 6.95 (d, J=8.4,2H); 6.90 (t, J=7.5); 3.71 (br. s, 2H); 2.13 (br. d, J=8.1, 1H);2.10-1.95 (m, 2H); 1.73 (br. d, J=8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr,cm⁻¹): 3258 (m), 2951 (m), 1660 (s), 1603 (s), 1500 (s), 1358 (m), 1306(m), 1277 (m), 1127 (m), 1092 (s), 892 (w), 828 (m), 749 (m), 691 (m),510 (m). MS (m/z): 379.0 ([M+H]⁺).

Example 229N(3)-[(4-Chlorophenyl)-amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (48 μl, 0.35 mmol), BOP reagent (152 mg, 0.35 mmol) and4-chlorophenylhydrazine hydrochloride (61 mg, 0.35 mmol) to give thetitle compound (98 mg, 69%). M.P.: 202-205° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.60 (s, 1H); 7.66 (d, J=9.0, 2H); 7.47 (d, J=9.0, 2H); 7.18 (d,J=8.6, 2H); 6.87 (d, 8.6, 2H); 3.71 (s, 2H); 2.13 (br. d, J=8.7, 1H);2.10-1.90 (m, 2H); 1.73 (br. d, J=9.0, 1H); 1.38-1.18 (m, 2H). IR (KBr,cm⁻¹): 3256 (m), 2995 (m), 2950 (m), 2870 (m), 1661 (s), 1595 (m), 1500(s), 1357 (m), 1278 (m), 1236 (m), 1128 (m), 1092 (s), 894 (w), 826 (m),658 (w), 610 (w), 503 (w). MS (m/z): 413.0 ([M+H]⁺).

Example 230N(3)-[(2,4-Dichlorophenyl)-amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0ml), Et₃N (57 μl, 0.42 mmol), BOP reagent (152 mg, 0.35 mmol) and2,4-dichlorophenylhydrazine hydrochloride (73 mg, 0.35 mmol)/furnishedthe title compound (53 mg, 34%). M. P.=180-182° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.54 (d, J=3.0, 1H); 7.66 (d, J=8.7, 2H); 7.47 (d, J=8.7, 2H);7.31 (d, J=2.1, 1H); 7.11 (dd, J=8.7, 2.1, 1H); 6.96 (d, J=8.7, 1H);6.51 (d, J=3.0, 1H); 3.71 (br. s, 2H); 2.13 (br. d, J=7.8, 1H); 2.0 (m,2H); 1.74 (br. d, J=9.0, 1H); 1.232-1.25 (m, 2H). IR (KBr, cm⁻¹): 3301(m), 2993 (m), 2873 (m), 1674 (s), 1595 (w), 1542 (m), 1499 (s), 1352(m), 1304 (m), 1232 (m), 1021 (m), 1049 (m), 814 (m).

Example 231N(3)-[(3,4-Dichlorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0ml), Et₃N (0.193 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and3,4-dichlorophenylhydrazine hydrochloride (148 mg, 0.69 mmol) gave thetitle compound (222 mg, 64.5%). M.P.: 235-237° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.50 (s, 1H); 7.67 (d, J=9.0, 2H); 7.48 (d, J=9.0, 2H); 7.28(d, J=8.4, 1H); 7.05 (d, J=2.4, 1H); 6.79 (dd, J=8.4, 2.4, 1H); 6.19(br. s, 1H); 3.70 (s, 2H); 2.14 (br. d, J=8.5, 1H); 2.10-1.90 (m, 2H);1.7 (br. d, J=8.5, 1H); 1.30-1.18 (m, 2H). IR (KBr, cm⁻¹): 3250 (m),2995 (w), 2968 (w), 2946 (w), 2869 (m), 1667 (s), 1650 (s), 1598 (m),1500 (s), 1475 (s), 1353 (m), 1277 (m), 1092 (m), 828 (m), 610 (w). MS(m/z): 449.0 ([M+H]⁺).

Example 232N(3)-[(2-Fluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0ml), Et₃N (0.193 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and2-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) gave the titlecompound (240 mg, 87%). M.P.: 91° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):8.50 (s, 1H); 7.65 (d, J=7.2, 2H); 7.46 (d, J=7.2, 2H); 6.95-7.10 (m,3H); 6.80-6.90 (m, 1H); 6.40 (br. s, 1H); 3.70 (br. s, 2H); 2.14 (br. d,J=9.0, 1H); 2.05-1.90 (m, 2H); 1.70 (br. d, J=9.0, 1H); 1.30-1.17 (m,2H). IR (KBr, cm⁻¹): 3292 (m), 2925 (m), 2870 (m), 1676 (s), 1502 (s),1351 (m), 1276 (m), 1194 (m), 1091 (s), 831 (s). MS (m/z): 397.0([M+H]⁺).

Example 233N(3)-[(3-Fluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0ml), Et₃N (0.193 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and3-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) yielded thetitle compound (158 mg, 58%). M.P.: 199° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.50 (s, 1H), 7.70 (d, J=9.0, 2H); 7.50 (d, J=9.0, 2H); 7.30-7.10(m, 1H); 6.70-6.50 (m, 3H); 6.20 (br. s, 1H); 3.70 (s, 2H); 2.14 (br. d,J=9.0, 1H); 2.10-1.90 (m, 2H); 1.73 (br. d, J=9.0, 1H); 1.35-1.18 (m,2H). IR (KBr, cm⁻¹): 3257 (m), 2952 (w), 2872 (w), 1663 (s), 1619 (m),1597 (m), 1501 (s), 1358 (m), 1266 (m), 1092 (m), 827 (m). MS (m/z):397.1 ([M+H]⁺).

Example 234N(3)-[(4-Fluorophenyl)-amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0ml), Et₃N (0.193 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and4-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) furnished thetitle compound (179 mg, 65%). M.P.: 212° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.50 (s, 1H); 7.70 (d, J=9.0, 2H); 7.50 (d, J=9.0, 2H); 7.00-6.80(m, 4H); 3.70 (s, 2H); 2.14 (br. d, J=9.0, 1H); 2.07-1.90 (m, 2H); 1.73(br. d, J=9.0, 1H); 1.35-1.18 (m, 2H). IR (KBr, cm⁻¹): 3268 (m), 2986(w), 2950 (w), 1663 (m), 1502 (s), 1359 (m), 1214 (w), 1092 (m), 827(m), 504 (w). MS (m/z): 397.0 ([M+H]⁺).

Example 235N(3)-[(2,4-Difluorophenyl)amino]-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 1.6 (200 mg, 0.69 mmol), DMF(2.0 ml), Et₃N (0.19 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and2,4-difluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) to givethe title compound (160 mg, 56%). M.P.: 1.18-120° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.50 (br. s, 1H); 7.70 (d, J=8.7, 2H); 7.50 (d, J=8.7,2H); 7.10-6.70 (m, 3H); 6.25 (br. s, 1H); 3.70 (s, 2H); 2.14 (br. d,J=8.7, 1H); 2.08-1.95 (m, 2H); 1.70 (br. d, J=8.7, 1H); 1.35-1.20 (m,2H). IR (KBr, cm⁻¹): 3422 (m), 3286 (m), 2925 (m), 2871 (w), 1666 (m),1501 (s), 1093 (m), 961 (m), 831 (m). MS (m/z): 417.1 ([M+H]⁺).

Example 236N(3)-(N′,N′-Diphenylamino-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0ml), Et₃N (0.19 ml, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) andN,N-diphenylhydrazine hydrochloride (113 mg, 0.69 mmol) gave the titlecompound (250 mg, 79.4%). M.P.: 193-195° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.98 (s, 1H); 7.66 (d, J=9.0, 2H); 7.45 (d, J=9.0, 2H); 7.40-7.20(m, 8H); 7.00 (m, 2H); 3.74 (br. s, 1H); 3.71 (br. s, 1H); 2.14 (br. d,J=8.7, 1H); 2.05-1.95 (m, 2H); 1.70 (br. d, J=8.7, 1H); 1.30-1.18 (m,2H). IR (KBr, cm⁻¹): 3232 (w), 2924 (m), 1664 (m), 1590 (m), 1497 (s),1357 (m), 1223 (m), 1092 (m), 828 (w). MS (m/z): 455.0 ([M+H]⁺).

Example 237N(3)-Cyclohexyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) andcyclohexylamine (33 μl, 0.31 mmol) gave the title compound (104 mg,83%). M.P.: 157-160° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (s, 1H);7.46 (d, J=8.0, 1H); 7.37 (d, J=8.0, 1H); 6.70 (br. d, J=8.1, 1H);4.05-3.85 (m, 1H); 3.75 (br. s, 1H); 3.36 (br. s, 2.13 (d, J=8.1, 1H);2.00-1.85 (m, 4H); 1.70-1.58 (m, 4H); 1.46-1.15 (m, 7H). IR (KBr, cm⁻¹):3398 (m), 2923 (m), 2850 (m), 1658 (s), 1543 (s), 1520 (s), 1485 (m),1343 (m), 1249 (m), 1122 (m), 1105 (m), 836 (m).

Example 238N(3)-Cyclohexylmethyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andcyclohexanemethylamine (40 μl, 0.31 mmol) furnished the title compound(90 mg, 69%). M.P.: 111-113° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56(br. s, 1H); 7.45 (d, J=8.7, 1H); 7.39 (br. d, J=8:7, 1H); 6.88 (br. t,J=6.3, 1H): 3.77 (br. s, 1H); 3.36 (br. s, 1H); 3.32-3.18 (m, 2H); 2.13(br. d, J=8.6, 1H); 2.00-1.50 (m, 9H); 1.25-1.11 (m, 5H); 1.00-0.80 (m,2H). IR (KBr, cm⁻¹): 3291 (m), 2922 (s), 2948 (m), 1643 (s), 1553 (m),1501 (s), 1486 (s), 1445 (m), 1351 (m), 1274 (m), 1241 (m), 1107 (m),1074 (m), 869 (m), 831 (m), 800 (m), 623 (m). MS (m/z): 418.1 ([M+H]⁺).

Example 239N(3)-(N,N-Dicyclohexylamino)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andN,N-dicyclohexylhydrazine (121 mg, 0.31 mmol) gave the title compound(70 mg, 45%). 127-130° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d,J=2.1, 1H); 7.48 (d, J=8.7, 1H); 7.35 (dd, J=8.7, 2.1, 1H); 7.33 (br. s,1H); 3.78 (s, 1H); 3.37 (s, 1H); 2.84 (br. s, 2H); 2.12 (br. d, J=8.4,1H); 1.97-1.80 (m, 6H); 1.80-1.58 (m, 6H); 1.40-1.00 (m, 13H). IR (KBr,cm⁻¹): 3328 (m); 2932 (s), 2854 (s), 1693 (s), 1537 (m), 1501 (m), 1482(m), 1345 (m), 1229 (m), 1102 (m), 1079 (m), 867 (m), 837 (m). MS (m/z):501.50 ([M+H]⁺).

Example 240N(3)-(4H-1,2,4-triazol-4-yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (42 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and4-amino-1,2,4-triazole (26 mg, 0.31 mmol) gave the title compound (38mg, 32%). M.P.: 231-233° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 11.95 (s,1H); 8.72 (s, 2H); 8.0 (d, J=2.1, 1H); 7.71 (d, J=8.4, 1H); 7.67 (dd,J=8.4, 2.1, 1H); 3.58 (br. s, 1H); 3.41 (s, 1H); 2.05 (br. d, J=8.7,1H); 1.98-1.90 (m, 2H); 1.71 (d, J=8.7, 1H); 1.24-1.08 (m, 2H). IR (KBr,cm⁻¹): 3125 (w), 3090 (m), 2997 (m), 2876 (m), 1699 (s), 1506 (s), 1350(m), 1129 (m), 1065 (s), 923 (w), 826 (w). MS (m/z): 389.3 ([M+H]⁺).

Example 241 N(3)-(1,3,3-Trim ethylbicyclo[2.2.1]hept-2-yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and(1S)-2endo-amino-1,3,3-trimethylbicyclo[2.2.1]heptane [prepared asdescribed by Suchocki et. al. in J. Med. Chem. 1991, 34, 1003-1010 (46mg, 0.34 mmol)] gave the title compound (76 mg, 54%). M.P.: 156-159° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d, J=2.1, 1H); 7.47 J=8.4, 1H);7.38 (dd, J=8.4, 2.1, 1H); 6.91 (br. d, J=8.4, 1H); 3.76 (br. s, 2H);3.38 (br. s, 1H); 2.12 (br. d, J=7.5, 1H); 2.00-1.84 (m, 2H); 1.80-1.58(m, 4H); 1.02 (m, 12H); 0.85 (s, 3H). IR (KBr, cm⁻¹): 3420 (m), 2954(s), 2869 (m), 1677 (s), 1538 (s), 1483 (s), 1386 (m), 1229 (m), 1161(m), 1113 (m), 1078 (s), 823 (w), 798 (w). MS (m/z): 458.10 ([M+H]⁺).

Example 242N(3)-(Adamantan-1yl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (0.51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and1-adamantylamine (46 mg, 0.31 mmol) furnished the title compound (108mg, 76%). M.P.: 201-20° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d,J=1.8, 1H); 7.45 (d, J=8.4, 2H); 7.37 (dd, J=8.4, 1.8, 1H); 6.60 (br. s,1H); 3.75 (br. s, 1H); 3.35 (br. s, 1H); 2.13 (br. s, 10H); 2.02-1.80(m, 2H); 1.70 (br. s, 7H); 1.40-1.13 (m, 2H). IR (cm⁻¹, KBr): 3400 (s),2907 (s), 2851 (m), 1667 (s), 1542 (s), 1516 (s), 1483 (s), 1452 (m),1359 (m), 1289 (w), 1230 (m), 1105 (m), 862 (w), 832 (m). MS (m/z):456.3 ([M+H]⁺).

Example 243N(3)-Phenyl-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (42 μl, 0.30 mmol), BOP reagent (12.1 mg, 0.31 mmol) andaniline (28 0.31 mmol) gave the title compound (90 mg, 71%). M.P.:66-68° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.63 (br. s, 1H); 7.68 (d,J=8.1, 2H); 7.59 (d, J=2.1, 1H); 7.49 (d, J=8.4, 1H); 7.41 (dd, J=8.4,2.1, 1H); 7.34 (t, J=8.1, 2H); 7.11 (t, J=7.5, 1H); 3.81 (br. s, 1H);3.39 (br. s, 1H); 2.16 (br. d, J=9.0, 1H); 2.05-1.86 (m, 2H); 1.73 (d,J=8.7, 1H); 1.35-1.15 (m, 2H). IR (KBr, cm⁻¹): 3382 (m), 2948 (m), 2869(m), 1681 (s), 1596 (s), 1542 (s), 1500 (s), 1434 (s), 1380 (m), 1347(m), 1321 (m), 1282 (m), 1237 (m), 1218 (m), 1159 (m), 1096 (m), 1077(m), 810 (m). MS (m/z): 398.1 ([M+H]⁺).

Example 244N(3)-(2,4-Difluorophenyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (57 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and2,4-difluoroaniline (31 μl, 0.31 mmol) yielded the title compound (62mg, 46%). M.P.: 152-155° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.79 (br. s,1H); 8.50-8.40 (m, 1H); 7.59 (d, J=2.1, 1H); 7.48 (d, i=8.4, 1H); 7.41(dd, J=8.4, 2.1, 1H); 6.95-6.82 (m, 2H); 3.79 (br. s, 1H); 3.40 (br. s,1H); 2.17 (br. d, J=8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (d, J=8.7, 1H);1.35-1.15 (m, 2H). IR (KBr, cm⁻¹): 3389 (s), 2993 (m), 2874 (m), 1685(s), 1543 (s), 1505 (s), 1428 (m), 1345 (m), 1123 (m), 1102 (m), 1085(m), 961 (w), 852 (w), 619 (w). MS (m): 434.0 ([M+H]⁺).

Example 245

N(3)-(2-Fluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and2-fluorobenzylamine (35 μl, 0.31 mmol) gave the title compound (55 mg,41%). M.P.: 54° C. (fuses). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (br. s,1H); 7.50-7.30 (m, 3H); 7.28-7.20 (m, 2H); 7.15-7.00 (m, 2H); 4.65 (br.d, J=5.1, 2H); 3.77 (br. s, 1H); 3.37 (br. s, 1H); 2.12 (br. d, J=7.5,1H); 1.99-1.84 (m, 2H); 1.69 (br. d, J=8.4, 1H); 1.28-1.15 (m, 2H). IR(KBr, cm⁻¹): 3419 (m), 2950 (m), 2874 (m), 1668 (s), 1548 (s), 1487 (s),1455 (s), 1346 (m), 1275 (m), 1229 (s), 1107 (s), 832 (n). MS (m/z):430.10 ([M+H]⁺).

Example 246N(3)-(4-Fluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and4-fluorobenzylamine (35 μl, 0.31 mmol) gave the title compound (90 mg,68%), M.P.: 106-108° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d, J=2.1,1H); 7.41 (d, J=8.4, 1H); 7.39-7.25 (m, 3H); 7.15 (br. t, J=6.6, 1H);7.00 (t, J=8.7, 2H); 4.54 (dd, J=17.0, 6.6, 1H); 4.59 (dd, J=17.0, 6.6,1H); 3.77 (br. s, 1H); 3.36 (br. s, 1H); 2.12 (br. d, J=9.0, 1H);2.10-1.82 (m, 2H), 1.70 (br. d, J=9.0, 1H); 1.32-1.10 (m, 2H). IR (KBr,cm⁻¹): 3277 (m), 2951 (m), 2979 (m), 2871 (m), 1648 (s), 1551(m), 1510(s), 1350 (m), 1273 (m), 1223 (s), 1108 (m), 1076 (w), 833 (m). MS(m/z): 432.1 ([M+H]⁺).

Example 247 N(3)-(2,4-Difluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,67-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and2,4-difluorobenzylamine (36 μl, 0.31 mmol) gave the title compound (93mg, 67%). M.P.: 73-76° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d,J=1.8, 1H); 7.40 (m, 3H); 7.20 (br. s, 1H); 6.90-6.75 (m, 2H); 4.50-4.70(m, 2H); 3.77 (br. s, 1H); 3.36 (br. s, 1H); 2.12 (br. d, J=8.7, 1H);2.02-1.86 (m, 2H); 1.69 (d, J=8.7, 1H); 1.14 (br. d, J=9.0, 2H). IR(KBr, cm⁻¹): 3421 (w), 3283 (m), 2996 (m), 2926 (w), 1648 (s), 1552(m),1505 (s), 1487 (s), 1455 (s), 1280 (m), 1138 (m), 1117 (m), 1098 (m),832 (m), 964 (w), 851 (w), 332 (w). MS (m/z): 448.10 ([M+H]⁺).

Example 248N(3)-(2,6-Difluorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (0.51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and2,6-difluorobenzylamine (36 mg, 0.31 mmol) furnished the title compound(74 mg, 53%). M.P.: 130-133° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.50-7.33 (m, 2H); 7.29-7.06 (m, 2H); 6.94-6.82 (m, 2H); 4.78-4.61 (m,2H); 3.78 (br. s, 1H); 3.35 (br. s, 1H); 2.10 (br. d, J=8.7, 1H);2.04-1.81 (m, 2H); 1.68 (d, J=8.7, 1H); 1.38-1.10 (m, 2H). IR (cm⁻¹,KBr): 3305 (m), 2988 (w), 2971 (w), 2945 (w), 2868 (w), 1672 (s), 1660(s), 1593 (s), 1545 (s), 1498 (s), 1406 (m), 1397 (m), 1355 (m), 1310(w), 1240 (m), 1218 (w), 1120 (w), 1189 (s), 1048 (w), 1008 (w), 829(s). MS (m/z): 448.1 ([M+H]⁺).

Example 249N(3)-(2-Chlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and2-chlorobenzylamine (37 μl, 0.31 mmol) gave the title compound (102 mg,74%). M.P.: 117-120° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d, J=2.4,1H); 7.50-7.30 (m, 4H); 730-7.16 (m, 3H); 4.67 (dd, J=17, 6.3, 1H); 4.72(dd, J=17.0, 6.3, 1H); 3.77 (br. s, 1H); 3.36 (br. s, 1H); 2.12 (br. d,J=8.6, 1H); 2.00-1.86 (m, 2H); 1.68 (br. d, J=8.6, 1H); 1.31-1.13 (m,2171). IR (KBr, cm⁻¹): 3309 (m), 2998 (m), 2968 (m), 2951 (m), 2925 (m),2869 (m), 1640 (s), 1564 (s), 1504 (s), 1487 (s), 1442 (m), 1346 (m),1281 (m), 1241 (m), 1110 (m), 1056 (m), 870 (m), 832 (m). MS (m/z):448.1 ([M+H]⁺).

Example 250N(3)-(4-Chlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and4-chlorobenzylamine (37 μl, 0.31 mmol) gave the title compound (108 mg,78%). M.P.: 139-142° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d, J=2.2,1H); 7.42 (d, 8.4, 1H); 7.36 (dd, J=8.4, 2.2, 1H); 7.29 (s, 4H); 7.16(br. t, J=5.1, 1H); 4.65-4.47 (m, 2H); 3.77 (br. s, 1H); 3.36 (br. s,1H); 2.12 (br. d, J=8.6, IR); 2.0-1.85 (m, 2H); 1.70 (br. d, J=8.6, 1H);1.32-1.15 (m, 2H). IR (KBr, cm⁻¹): 3290 (m), 2934 (m), 2869 (m), 1652(s), 1553 (s), 1489 (s), 1436 (m), 1351 (m), 1276 (m), 1249 (m), 1142(m), 1076 (m), 851 (m), 799 (m), 707 (m), 654 (m), 623 (m). MS (m/z):448.2

Example 251N(3)-(2,4-Dichlorobenzyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and2,4-dichlorobenzylamine (41 μl, 0.31 mmol) gave the title compound (118mg, 79%). M.P.: 57-59° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (s, 1H);7.45-7.37 (m, 4H); 7.27-7.20 (m, 3H); 4.60 (br. d, J=4.8, 2H); 3.76 (s,1H); 3.37 (s, 1H); 2.12 (br. d, J=8.4, 1H); 2.05-1.86 (m, 2H); 1.71-1.65(br. d, J=8.4, 1H); 1.26-1.13 (m, 2H). IR (KBr, cm⁻¹): 3337 (m), 2948(m), 2870 (m), 1737 (m), 1666 (s), 1545 (s), 1483 (s), 1381 (m), 1347(m), 1236 (s), 1104 (s), 1078 (m), 1046 (m), 865 (m), 832 (s). MS (m/z):482.3 ([M+H]⁺).

Example 252N(3)-[S-(1-phenylethyl)]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and(S)-(−)-1-phenylethylamine (39 0.31 mmol) gave the title compound (74mg, 66%). M.P.: 91-94° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (d,J=2.1, 1H); 7.47-7.20 (m, 7H); 7.08 (d, J=7.5, 1H); 5.38-5.22 (m, 1H);3.75 (br. s, 1H); 3.35 (br. s, 1H); 2.11 (br. t, J=8.7, 1H); 2.00-1.80(m, 2H); 1.69 (br. s, 1H), 1.58 (d, J=6.9, 3H); 1.40-1.08 (m, 1H). MS(m/z): 426.10 ([M+H]⁺).

Example 253N(3)-[R-(1-phenylethyl)]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andR-(+)-1-phenethylamine (33 μl, 0.31 mmol) gave the title compound (66mg, 50%). M.P.: 89-92° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d,J=2.1, 1H); 7.50-7.20 (m, 7H); 7.08 (d, J=7.8, 1H); 5.30 (m, 1H); 3.75(br. s, 1H); 3.35 (br. s, 1H); 2.10 (t, J=9.0, 1H); 2.00-1.80 (m, 2H);169 (br. s, 1H); 1.58 (d, J=6.9, 3H); 1.40-1.10 (m, 2H). IR (KBr, cm⁻¹):3411 (m), 3247 (m), 2972 (m), 2952 (m), 2870 (m), 1638 (s), 1545 (m),1502 (s), 1483 (s), 1448 (m), 1378 (m), 1359 (m), 1239 (m), 1262 (m),1138 (m), 1101 (m), 1076 (m), 815 (w), 699 (m). MS (m/z): 426.0([M+H]⁺).

Example 254N(3)-(2-phenylethyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) andphenethylamine (38 μl, 0.31 mmol) gave the title compound (70 mg, 53%)as waxy solid. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d, J=1.8, 1H); 7.43(d, J=8.4, 1H); 7.36 (dd, J=8.4, 1.8, 1H); 7.35-7.19 (m, 5H); 6.91 (br.s, 1H); 3.75 (br. s, 1H); 3.70-3.60 (m, 2H); 3.36 (br. s, 1H); 2.90 (t,J=7.2, 2H); 2.12 (br. d, J=8.6, 1H); 2.01-1.84 (m, 2H); 1.69 (br. d,J=8.6, 1H); 1.31-1.13 (m, 2H).

Example 255N(3)-[2-(4-fluorophenyl)ethyl]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and4-fluorophenethylamine (40 μl, 0.31 mmol) yielded the title compound(100 mg, 73%) as a glassy paste. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56(d, J=2.1, 1H); 7.41 (d, J=8.4, 1H); 7.37 (d, J=8.4, 2.1, 1H); 7.19 (dd,J=8.4, 5.4, 2H); 6.98 (t, J=8.7, 2H); 6.90 (br. t, J=4.6, 1H); 3.75 (br.s, 1H); 3.71-3.57 (m, 2H); 3.36 (br. s, 1H); 2.90 (t, J=7.5, 2H); 2.12(br. d, J=8.7, 1H); 2.02-1.86 (m, 2H); 1.69 (br. d, J=8.7, 1H);1.31-1.13 (m, 2H).

Example 256N(3)-Phenylamino-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andphenylhydrazine hydrochloride (30 μl, 0.31 mmol) gave the title compound(84 mg, 66%). M.P.: 182-185° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.48(br. s, 1H); 7.58 (d, J=1.8, 1H); 7.48 (d, J=8.5, 1H); 7.40 (dd, J=8.5,1.8, 1H); 7.26-7.20 (m, 3H); 7.00-6.82 (m, 3H); 3.73 (br. s, 1H); 3.40(br. s, 1H); 2.13 (br. d, J=8.1, 1H); 1.97-1.90 (m, 2H); 1.71 (br. d,J=9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm⁻¹): 3251 (s), 2996 (m), 2947(m), 2870 (m), 1663 (s), 1604 (m), 1542 (m), 1498 (s), 1483 (s), 1352(m), 1279 (m), 1230 (m), 1231 (m), 1111 (m), 1083 (m), 1060 (m), 937(m), 899 (m), 889 (m), 867 (m). MS (m/z): 413.0 ([M+H]⁺).

Example 257N(3)-[(2-Chlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (107 μl, 0.77 mmol), BOP reagent (136 mg, 0.31 mmol) and2-chlorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) gave the titlecompound (78 mg, 57%). M.P.: 180-183° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):8.49 (br. s, 1H); 7.59 (d, J=2.4, 1H); 7.48 (d, J=8.4, 1H); 7.41 (dd,J=8.4, 2.4, 1H); 7.29 (d, J=8.0, 1H); 7.14 (t, J=7.8, 1H); 7.03 (d,J=8.1, 1H); 6.83 (t, J=8.0, 1H); 6.55 (br. s, 1H); 3.73 (br. s, 1H);3.40 (br. s, 1H); 2.13 (br. d, J=9.0, 1H); 2.01-1.87 (m, 2H); 1.70 (br.d, J=9.0, 1H); 1.30-1.16 (m, 2H). IR (KBr, cm⁻¹): 3255 (br., m), 2959(w), 2874 (w), 1667 (s), 1508 (s), 1346 (m), 1279 (m), 1110 (m), 1079(m), 1066 (m), 862 (w). MS (m/z): 448.9 ([M+H]⁺).

Example 258N(3)-[N-(2-Chlorophenyl)-N-methylamino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (0.51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andN-(2-chlorophenyl)-N-methylhydrazine hydrochloride (59 mg, 0.31 mmol)furnished the title compound (104 mg, 70%). M.P.: 121-124° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 8.82 (br. s, 1H); 7.56 (d, J=2.1, 2H); 7.45 (d,J=8.4, 1H); 7.42 (dd, J=8.1, 1.5, 1H); 7.38 (dd, j=8.4, 2.1, 1H); 7.31(dd, J=8.1, 1.5, 1H); 7.24 (td, J=8.1, 1.5, 1H); 6.99 (td, J=8.1, 1.51H); 3.70 (br. s, 1H); 3.37 (br. s, 4H); 2.09 (br. d, J=8.4, 1H);2.00-1.82 (m, 2H); 1.67 (br. d, J=8.7, 1H); 1.30-1.10 (m, 2H). IR (cm⁻¹,KBr): 3404 (s), 3253 (m), 2951 (w), 2868 (w), 1654 (s), 1587 (w), 1545(w), 1500 (s), 1484 (s), 1475 (s), 1443 (m), 1348 (w), 1276 (m), 1236(m), 1122 (m), 1107 (m), 1052 (m), 832 (s). MS (m/z): 461.0 ([M+H]⁺).

Example 259N(3)-[(4-Chlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0ml), Et₃N (189 μl, 1.36 mmol), BOP reagent (273 mg, 0.62 mmol) and4-chlorophenylhydrazine hydrochloride (110 mg, 0.62 mmol) gave the titlecompound (195 mg, 70%). M.P.: 141-144° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.47 (s. 1H); 7.59 (d, J=1.8, 1H); 7.48 (d, J=8.3, 1H); 7.40 (dd;J=8.3, 1.8, 1H); 7.18 (d, J=8.7, 2H); 6.87 (d, J=8.7, 2H); 6.17 (br. s,1H); 3.72 (s, 1H); 3.40 (s, 1H); 2.15 (br. d, J=8.7, 1H); 1.99-1.88 (m,2H); 1.70 (br. d, J=8.7, 1H); 1.26-1.19 (m, 2H). IR (KBr, cm⁻¹): 3271(s), 2991 (m), 1667 (m), 1596 (m), 1505 (m), 1491 (m), 1348 (m), 1276(m), 1230 (m), 1080 (m), 1065 (m), 889 (m), 824 (s). MS (m/z): 447.0([M+H]⁺).

Example 260N(3)-[(2,4-Dichlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0ml), Et₃N (189 μl, 1.36 mmol), BOP reagent (273 mg, 0.62 mmol) and2,4-dichlorophenylhydrazine hydrochloride (132 mg, 0.62 mmol) to givethe title compound (205 mg, 69%). M.P.: 187-190° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.47 (d, J=3.0, 1H); 7.59 (d, J=2.1, 1H); 7.47 (d,J=8.6, 1H); 7.40 (dd, J=8.6, 2.1, 1H); 7.30 (d, J=2.4, 1H); 7.11 (dd,J=8.7, 1H); 6.95 (d, J=9.0, 1H); 6.49 (d, J=3.0, 1H); 3.71 (s, 1H); 3.39(s, 1H); 2.12 (br. d, J=9.3, 1H); 1.97-1.90 (m, 2H); 1.70 (br. d, J=9.3,1H); 1.25-1.15 (m, 2H). IR (KBr, cm⁻¹): 3348 (m), 3191 (m), 2984 (m),2968 (m), 2873 (w), 1661 (s), 1588 (m), 1557 (m), 1495 (s), 1343 (m),1279 (m), 1108 (m), 1078 (m), 1068 (m), 861 (m).

Example 261N(3)-[(2,4-dichlorophenyl)-N-methylamino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (0.51 μl, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) andN-(2,4-dichlorophenyl)-N-methylhydrazine (59 mg, 0.31 mmol) furnishedthe title compound (97 mg, 63%). M.P.: 135-138° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 8.81 (br. s, 1H); 7.57 (d, J=1.8, 1H); 7.42 (d, J=1H); 7.40(dd, J=8.3, 1.8, 1H); 7.35 (d, J=8.3, 1H); 7.31 (d, J=2.4, 1H); 7.21(dd, 8.3, 2.4, 1H); 3.69 (br. s, 1H); 3.35 (br. s, 4H); 2.09 (br. d,J=9.0, 1H); 2.00-1.80 (m, 2H); 1.67 (br. d, J=9.0, 1H); 1.35-1.20 (m,2H). IR (cm⁻¹, KBr): 3348 (s), 3081 (w), 2963 (m), 2871 (w), 1683 (s),1586 (w), 1565 (w), 1533 (m), 1505 (s), 1482 (s), 1470 (s), 1438 (m),1345 (m), 1122 (m), 1105 (m), 1085 (m), 1464 (s), 1049 (m), 814 (m). MS(m/z): 495.0 ([M+H]⁺).

Example 262N(3)-[(3,4-Dichlorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (200 mg, 0.619 mmol), DMF(2.0 ml), Et₃N (189 μl, 1.361 mmol), BOP reagent (273 mg, 0.619 mmol)and 3,4-dichlorophenylhydrazine hydrochloride (132 mg, 0.619 mmol)furnished the title compound (205 mg, 69%). 176-179° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.48 (s, 1H); 7.59 (d, J=2.1, 1H); 7.48 (d, J=8.4, 1H);7.40 (dd, J=8.4, 2.1, 1H); 7.26 (d, J=8.7, 1H); 7.03 (d, J=2.7, 1H);6.77 (dd, J=2.7, 1H); 6.22 (br. s, 1H); 3.72 (br. s, 1H); 3.40 (br. s,1H); 2.13 (br. d, J=9.0, 1H); 2.03-1.88 (m, 2H); 1.70 (br d, J=9.0, 1H);1.30-1.16 (m, 2H). IR (KBr, cm⁻¹): 3314 (m), 2951 (m), 2870 (m), 1678(s), 1602 (m), 1511 (s), 1475 (s), 1384 (m), 133.9 (m), 1253 (m), 1225(m), 1126 (s), 1062 (s), 863 (m), 819 (s). MS (m/z): 481.0 ([M+H]⁺).

Example 263N(3)-[(2-Bromophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (103 μl, 0.74 mmol), BOP reagent (136 mg, 0.31 mmol) and2-bromophenylhydrazine hydrochloride (69 mg, 0.31 mmol) yielded thetitle compound (115 mg, 76%). M.P.: 159° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.50 (d, J=3.3, 1H); 7.59 (d, J=2.4, 1H); 7.50-7.39 (m, 3 H); 7.20(t, J=7.7, 1H); 7.01 (d, J=6.9, 1H); 6.77 (t, J=7.5, 1H); 6.52 (d,J=3.3, 1H); 3.73 (s, 1H); 3.40 (s, 1H); 2.14 (br. d, J=8.7, 1H);2.02-1.91 (m, 2H); 1.70 (br d, J=8.7, 1H); 1.30-1.19 (m, 2H). IR (KBr,cm⁻¹): 3256 (m), 2925 (m), 2859 (m), 1666 (s), 1505 (s), 1344 (m), 1278(m), 1232 (m), 1110 (m), 1079 (m), 1064 (m), 742 (m). MS (m/z): 491:0([M+H]⁺).

Example 264N(3)-[(2-Fluorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0ml), Et₃N (0.2.0 ml, 1.49 mmol), BOP reagent (273 mg, 0.62 mmol) and2-fluorophenylhydrazine hydrochloride (100 mg, 0.62 mmol) gave the titlecompound (96 mg, 72%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.51 (br. s, 1H);7.59 (d, J=2.1, 1H); 7.48 (d, J=8.6, 1H); 7.40 (dd, J=8.6, 2.1, 1H);7.10-6.95 (m, 3H); 6.90-6.80 (m, 1H); 3.73 (br. s, 1H); 3.40 (br. s,1H); 2.14 (br. d, J=9.0, 1H); 2.02-1.85 (m, 2H); 1.70 (d, J=9.0, 1H);1.30-1.15 (m, 2H). IR (KBr, cm⁻¹): 3256 (br. s), 2989 (m), 2959 (m),2873 (w), 1666 (s), 1618 (m), 1508 (s), 1456 (m), 1345 (m), 1279 (m),1243(m), 1194 (m), 1099 (s), 1063 (m), 863 (m).

Example 265N(3)-[(2,4-Difluorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (150 mg, 0.46 mmol), DMF (2.0ml), Et₃N (154 μl, 1.11 mmol), BOP reagent (205 mg, 0.46 mmol) and2,4-difluorophenylhydrazine hydrochloride (83 mg, 0.46 mmol) furnishedthe title compound (143 mg, 69%). M.P.: 157-160° C. ¹H-NMR (δ ppm,CDCl₃, 300 MHz): 8.50 (br. s, 1H); 7.59 (d, J=1.8, 1H); 7.47 (d, J=8.4,1H); 7.39 (dd, J=8.4, 1.8, 1H); 7.00 (dt, J=9.0, 5.4, 1H); 6.82 (td,J=8.4, 2.7, 1H); 6.72 (br. t, J=8.1, 1H); 3.72 (br. s, 1H); 3.40 (br. s.1H); 2.13 (br. d, J=8.4, 1H); 2.05-1.85 (m, 2H); 1.70 (d, J=8.4, 1H);1.30-1.15 (m, 2H). IR (KBr, cm⁻¹): 3358 (m), 3198 (m), 3061 (m), 2989(m), 2874 (m), 1664 (s), 1565 (m), 1520 (s), 1468 (m), 1382 (m), 1320(m), 1281 (m), 1262 (m), 1207 (m), 1123 (m), 1108 (m), 1077 (m), 959(m), 798 (m). MS (m/z): 449.0 ([M+H]⁺).

Example 266N(3)-[(3-Fluorophenyl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (103 μl, 0.74 mmol), BOP reagent (136 mg, 0.31 mmol) and3-fluorophenylhydrazine hydrochloride (50 mg, 0.31 mmol) yielded thetitle compound (98 mg, 74%). M.P.: 190° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.46 (s, 1H); 7.59 (d, J=2.4, 1H); 7.49 (d, J=8.4, 1H); 7.40 (dd,J=8.7, 2.4, 1H); 7.21-7.13 (m, 1H); 6.77-6.47 (m, 3H); 6.20 (br. s, 1H);3.73 (s, 1H); 3.40 (s, 1H); 2.14 (br. d, J=8.6, 1H); 2.02-1.88 (m, 2H);1.70 (br. d, J=8.6, 1H); 1.31-1.16 (m, 2H). IR (KBr, cm⁻¹): 3411 (s),3277 (s), 2986 (m), 2940 (m), 2870 (m), 1670 (s), 1615 (s), 1544 (s),1504 (s), 1469 (s), 1444 (s), 1475 (s), 1341(m), 1273 (n1), 1237 (m),1105 (m), 1081 (m), 835 (n). MS (m/z): 431.1 ([M+H]⁺).

Example 267N(3)-[(3-chloropyridin-2-yl)amino]-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (51 μl, 0.32 mmol), BOP reagent (129 mg, 0.32 mmol) and3-chloro-2-hydrazinopyridine (44 mg, 0.31 mmol.) to give the titlecompound (50 mg, 36%). M.P.: 95° C. (fuses). ¹H-NMR (δ ppm, CDCl₃, 300MHz): 9.40 (br. s, 1H); 8.10 (br. d, J=4.8, 1H); 7.60 (br. d, J=7.8,2H); 7.58-7.50 (m, 1H); 7.39 (br. d, J=8.1, 2H); 6.78 (dt, J=7.5, 2.4,1H); 3.72 (br. s, 1H); 3.41 (br. s, 1H); 2.15 (t, J=8.7, 1H), 2.00-1.85(m, 2H); 1.69 (br. d, J=8.7, 1H); 1.20-1.10 (m, 2H). IR (cm⁻¹, KBr):3368 (br. m), 2954 (m), 2870 (m), 1677 (s), 1591 (s), 1537 (m), 1498(s), 1470 (s), 1406 (m), 1252 (m), 1227 (m), 1125 (s), 1080 (m), 1033(m), 866 (w), 832 (m). MS (m/z): 448.0 ([M+H]⁺).

Example 268N(5)-piperidino-3-(2′,4′-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 ml),triethylamine (0.04 ml, 0.31 mmol), BOP reagent (136 mg, 0:31 mmol) and1-aminopiperidine (0.033 ml, 0.31 mmol) to give the title compound (62mg, 50%). ¹H-NMR (δ ppm, CDCl₃): 7.56 (d, J=2.1, 1H); 7.45 (d, J=8.4,1H); 7.37 (dd, J=8.4, 2.1, 1H); 3.76 (br. s, 1H); 3.36 (br. s, 1H); 2.91(br. s, 4H); 2.12 (br. d, J=10.2, 1H); 2.04-1.82 (m, 2H); 1.81-1.56 (m,5H); 1.50-1.38 (m, 2H); 1.34-1.10 (m, 2H).

Example 269N(5)-benzyl-3-(2′,4′-dichlorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized as per the procedure described forexample 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 ml),triethylamine (0.04 ml, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) andbenzylamine (0.033 ml, 0.31 mmol) to give the title compound (94 mg,74%). ¹H-NMR (δ ppm, CDCl₃): 7.55 (d, J=2.1, 1H); 7.42 (d, J=8.4, 1H);7.37-7.23 (m, 6H); 7.15 (br. s, 1H); 4.63 (dd, J=11.0, 5.0, 1H); 4.57(dd, J=11.0, 5.0, 1H); 3.78 (br. s, 1H); 3.36 (br. s, 1H); 2.13 (br. d,J=8.4, 1H); 2.04-1.82 (m, 2H); 1.70 (br. d, J=8.4, 1H); 1.35-1.11 (m,2H).

Example 270N(3)-Piperidino-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) and1-aminopiperidine (32 μl, 0.30 mmol) gave the title compound (52 mg,42%). M.P.: 236° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.73 (d, J=8.4, 1H);7.58 (br. s, 1H); 7.39-7.46 (m, 2H); 7.36-7.30 (m, 1H); 3.77 (br. s,1H); 3.35 (br. s, 1H); 2.85 (br. s, 4H); 2.15 (br. d, J=7.8, 1H);2.00-1.71 (m, 6H); 1.44-1.16 (m, 5H). IR (KBr, cm⁻¹): 3308 (m), 3000(m), 2940 (s), 2864 (m), 2793 (m), 1685 (s), 1540 (s), 1511 (s), 1484(s), 1449 (m), 1340 (w), 1229 (m), 1133 (m), 1123 (m), 1036 (m), 986(m), 904 (m), 832 (w). MS (m/z): 415.1 ([M+H]⁺).

Example 271N(3)-Cyclohexyl-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) andcyclohexylamine (39 μl, 0.34 mmol) gave the title compound (100 mg,80%). M.P.: 178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.26: (d, J=8.1,1H); 7.51-7.40 (m, 2H); 7.33 (br. t, J=8.1, 1H); 6.73 (br. d, J=8.4,1H); 3.85-4.05 (m, 1H); 3.77 (br. s, 1H); 3.35 (br. s, 1H); 2.15 (br. d,J=7.2, 1H); 2.00-1.85 (m, 4H); 1.80-1.65 (m, 4H); 1.50-1.14 (m, 7H). IR(KBr, cm⁻¹): 3413 (m), 2938 (s), 2854 (m), 1662 (s), 1541 (s), 1512 (s),1480 (s), 1450 (s), 1341 (m), 1299 (m), 1222 (m), 1159 (m), 1125 (m). MS(m/z): 414.0 ([M+H]⁺).

Example 272N(3)-Benzyl-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) andbenzylamine (32 μl, 0.30 mmol) gave the title compound (60 mg, 47%).M.P.: 110° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70 (d, J=8.4, 1H);7.45-7.16 (m, 9H); 4.61 (m, 2H); 3.79 (br. s, 1H); 3.56 (br. s, 1H);2.16 (br. d, J=8.7, 1H); 2.05-1.80 (m, 2H); 1.70 (br. d, J=8.7, 1H);1.35-1.15 (m, 2H). IR (KBr, cm⁻¹): 3419 (w), 3020 (s), 240.1 (w), 1661(w), 1549 (w), 1516 (w), 1484 (w), 1427 (w), 1343 (w), 1216 (s). MS(m/z): 422.0 ([M+H]⁺).

Example 273N(3)-Phenylamino-1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) andphenylhydrazine (30 μl, 0.30 mmol) gave the title compound (101 mg,80%). M.P.: 219° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.51 (br. s, 1H);7.50 (d, J=7.8, 1H); 7.60-7.41 (m, 2H); 7.36 (br. t, J=8.4, 1H); 7.34(t, J=7.8, 2H); 6.95 (d, J=7.8, 2H); 6.89 (t, J=7.5, 1H); 3.73 (br. s,1H); 3.39 (br. s, 1H); 2.16 (br. d, J=7.2, 1H); 2.00-1.85 (m, 2H); 7.70(d, J=8.7, 1H); 1.28-1.20 (m, 2H). IR (KBr, cm⁻¹) δ 3283 (m), 2992 (m),2959 (m), 2863 (w), 1675 (s), 1603 (m), 1542 (m), 1511 (s), 1497 (s),1438 (m), 1348 (m), 1281 (m), 1240 (m), 1136 (m), 1123 (m), 1084 (m),1029 (m), 888 (m). MS (m/z): 423.0 ([M+H]⁺).

Example 274N(3)-Piperidino-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 033 mmol) and1-aminopiperidine (33 0.30 mmol) furnished the title compound (124 mg,99%). M.P.: 173° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.60 (br. s, 4H);3.70 (br. s, 1H); 3.65 (br. s, 1H); 2.90 (br. s, 4H); 2.20 (br. d,J=7.14, 1H); 2.00 (br. d, J=8.6, 2H); 1.90-1.60 (m, 6H); 1.30-1.20 (m,3H). IR (KBr, cm⁻¹): 3408 (w), 3308 (w), 2929 (s), 2859 (m), 2780 (m),1692 (s), 1591 (m), 1541 (s), 1503 (s), 1489 (s), 1440 (m), 1401 (m),1348 (s), 1268 (m), 1226 (s), 1154 (m), 1122 (s), 1064 (m), 1006 (m),827 (s). MS (m/z): 415.1 ([M+H]⁺).

Example 275N(3)-Cyclohexyl-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) andcyclohexylamine (34 μl, 0.30 mmol) gave the title compound (91 mg, 73%).M.P.: 164° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.58 (s, 4H); 6.75 (br. d,J=8.1, 1H); 3.93 (m, 1H); 3.75 (br. s, 1H); 3.67 (br. s, 1H); 2.12 (br.d, J=8.4, 1H); 2.10-1.90 (m, 4H); 1.80-1.70 (m, 3H); 1.60-1.20 (m, 8H).IR (KBr, cm⁻¹): 3410 (m), 2922 (m), 2848 (m), 1667 (s), 1591 (w), 1546(s), 1504 (s), 1486 (s), 1450 (m), 1349 (m), 1224 (m), 1160 (m), 1122(m), 1065 (m), 1006 (m), 827 (m). MS (m/z): 414.1 ([M+H]⁺).

Example 276N(3)-Benzyl-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) and benzylamine (33 μl, 0.30 mmol) yielded the title compound (107 mg, 85%). M.P.:89° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56 (br. s, 4H); 7.40-7.22 (m,6H); 4.64 (d, J=5.4, 2H); 3.80 (br. s. 1H); 3.68 (br. s, 1H); 2.14 (br.d, J=8.1, 1H); 2.00 (br. d, J=5.7, 2H); 1.74 (d, J=8.4, 1H); 1.26-1.20(m, 2H). IR (KBr, cm⁻¹): 3321 (m), 2937 (m), 2868 (m), 1649 (s), 1590(m), 1551 (s), 1499 (s), 1455 (m), 1347 (s), 1275 (m), 1241 (m), 1121(m), 1070 (m), 1005 (m), 975 (m), 825 (m). MS (m/z): 422.1 ([M+H]⁺).

Example 277N(3)-Phenylamino-1(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (50 μl, 0.36 mmol), BOP reagent (146 mg, 0.33 mmol) andphenylhydrazine (29 μl, 0.30 mmol) furnished the title compound (90 mg,71%). M.P.: 138° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.54 (br. s, 1H);7.61 (s, 4H); 7.24 (t, J=7.8, 2H); 6.95 (d, J=8.4, 2H); 6.90 (t, J=7.2,1H); 3.72 (br. 2H); 2.13 (br. d, J=8.0, 1H); 1.99 (br. d, J=7.8, 2H);1.73 (br. d, J=8.0, 1H); 1.40-1.15 (m, 2H). IR (KBr, cm⁻¹): 3262 (m),2948 (m), 2869 (m), 1666 (s), 1603 (s), 1591 (s), 1545 (m), 1497 (s),1401 (m), 1357 (m), 1279 (m), 1252 (m), 1227 (m), 1124 (m), 1083 (m),1070 (m), 1005 (m), 894 (m). MS (m/z): 422.9 ([M+H]⁺).

Example 278N(3)-[(2-Fluorophenyl)amino]-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (63 μl, 0.45 mmol), BOP reagent (146 mg, 0.33 mmol) and2-fluorophenylhydrazine hydrochloride (48 mg, 0.30 mmol) furnished thetitle compound (50 mg, 38%). M.P.: 123° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.57 (br. s, 1H); 7.61 (s, 4H); 7.10-6.70 (m, 3N); 7.00-6.80 (m,1H); 3.71 (s, 2H); 2.17 (br. d, J=8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (d,J=8.7, 1H); 1.35-1.15 (m, 2H). MS (m/z): 441.1 ([M+H]⁺).

Example 279N(3)-Cyclohexyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0ml), Et₃N (61 μl, 0.44 mmol), BOP reagent (178 mg, 0.40 mmol) andcyclohexylamine (42 μl, 0.37 mmol) gave the title compound (72 mg, 56%).M.P.: 127° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.64-7.62 (m, 2H); 7.17(t, J=8.4, 2H); 6.75 (br. d, J=7.7, 1H); 4.05-3.80 (m, 1H); 3.75 (br. s,1H); 3.64 (br. s, 1H); 2.20-1.90 (br. s, 5H); 1.74-1.66 (m, 5H);1.44-1.10 (m, 6H). IR (KBr, cm⁻¹): 3352 (m), 3310 (w), 2934 (m), 2834(m), 1656 (s), 1642 (s), 1517 (s), 1499 (s), 1451 (m), 1350 (m), 1276(w), 1252 (w), 1223 (s), 1163 (m), 1123 (m), 842 (m). MS (m/z): 354.1([M+H]⁺).

Example 280N(3)-Benzyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0ml), Et₃N (61 μl, 0.44 mmol), BOP reagent (178 mg, 0.40 mmol) andbenzylamine (39 μl, 0.36 mmol) gave the title compound (43 mg, 33%).M.P.: 104° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.62 (br. s, 2H);7.38-7.00 (m, 8H); 4.63 (br. d, J=5.1, 2H); 3.78 (br. s, 1H); 3.66 (br.s, 1H); 2.12 (br. d, J=8.4, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J=8.4, 1H);1.40-1.10 (m, 2H). IR (KBr, cm⁻¹): 3411 (m), 3009 (w), 286.9 (w), 1670(s), 1543 (s), 1500 (s), 1492 (s), 1454 (m), 1416 (m), 1349 (s), 1276(m), 1226 (s), 1212 (s), 1164 (m), 1124 (m), 954 (w); 835 (s). MS (m/z):362.1 ([M+H]⁺).

Example 281N5-(Adamantan-2-yl)-3-(4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (124 μl, 0.88 mmol), BOP reagent (170 mg, 0.38 mmol) and2-adamantylamine hydrochloride (103 mg, 0.55 mmol) furnished the titlecompound (120 mg, 80%). M.P.: 196-198° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.69-7.63 (m, 2H); 7.17 (t, J=8.1, 2H); 4.23 (d, J=8.4, 1H); 3.75(br. s, 1H); 3.65 (br. s, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H),1.26-1.21 (m, 2H). IR (cm⁻¹, KBr): 3414 (s), 2979 (w), 2901 (s), 2851(s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347(w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m),1091 (m), 953 (w),833 (m). MS (m/z): 406.2 ([M+H]⁺).

Example 282N5-(1-Methyl-1-phenylethyl)-3-(4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (41 μl, 0.40 mmol), BOP reagent (170 mg, 0.38 mmol) andα,α-dimethylbenzylamine (75 mg, 0.55 mmol) furnished the title compound(77 mg, 54%). M.P.: 119-122° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.68-7.62 (m, 2H); 7.51-7.46 (m, 2H); 7.37-7.30 (m, 2H); 7.27-7.13 (m,3H); 3.70 (br. s, 1H); 3.63 (br. s, 1H); 2.08 (d, J=9.0, 1H), 1.95 (d,J=7.8, 2H); 1.84 (s, 6H); 1.68 (d, J=8.4, 1H), 1.23 (d, J=12.0, 211). IR(cm⁻¹, KBr): 3358 (m), 2972 (m), 2927 (m), 2870 (m), 1664 (s), 1605 (w),1542 (m), 1515 (s), 1489 (m), 1383 (w), 1357 (m), 1276 (m) 1219 (m),1136 (m), 1117 (m), 1093 (m), 1031 (w), 1088 (w), 949 (w), 858 (w), 839(m). MS (m/z): 390.0 (M+H⁺).

Example 283N5-(Adamantan-1-yl)-3-(4-fluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (41 μl, 0.40 mmol), BOP reagent (170 g, 0.38 mmol) and1-adamantylamine (83 mg, 0.54 mmol) furnished the title compound (127mg, 85%). M.P.: 189-191° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66-7.60(m, 2H); 7.19-7.12 (m, 2H); 6.66 (br. s, 1H); 3.74 (br. s, 1H); 3.63(br. s, 1H); 2.15-2.10 (m, 9H); 1.97 (d, J=8.7, 2H); 1.75-1.68 (m, 8H);1.30-1.20 (m, 2H). IR (cm⁻¹, KBr): 3361 (m), 2986 (m), 2909 (s), 2849(m), 1658 (s), 1517 (s), 1550 (s), 1493 (s), 1445 (m), 1412 (m), 1308(w), 1289 (w), 1278 (w), 1256 (s), 1219 (s), 868 (m). MS (m/z): 406.1([M++H]⁺).

Example 284N(3)-Phenylamino-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.37 mmol), DMF (1.0ml), Et₃N (61 μl, 0.44 mmol), BOP reagent (178 mg, 0.40 mmol) andphenylhydrazine (36 μl, 0.37 mmol) gave the title compound (72 mg, 54%).M.P.: 163° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.55 (s, 1H); 7.69 (dd,J=9.3, 5.2, 2H); 7.27-7.16 (m, 4H); 6.95 (d, J=7.5, 2H); 6.90 (t, J=7.2,1H); 3.73 (br. s, 1H); 3.69 (br. s, 1H); 2.15 (br. d, J=9.0, 1H);2.06-1.99 (m, 2H); 1.73 (d, J=8.7, 1H); 1.25 (br. d, J=7.2, 2H). IR(KBr, cm⁻¹): 3376 (m), 2991 (m), 2952 (m), 2871 (m), 1674 (s), 1604 (s),1517 (s), 1497 (s), 1441 (m), 1350 (m), 1279 (m), 1223 (s), 1154 (m),1127(m), 1093 (m), 1083 (m), 1066 (m), 1041 (w), 889 (m), 841 (m). MS(m/z): 363.1 ([M+H]⁺).

Example 285N(3)-Phenylamino-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (44 μl, 0.32 mmol), BOP reagent (125 mg, 0.28 mmol) andphenylhydrazine (34 μl, 0.34 mmol) gave the title compound (87 mg, 44%).M.P.: 161° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.50 (br. s, 1H); 7.70 (m,1H); 7.24 (t, J=7.8, 2H); 7.09-6.99 (m, 2H); 6.99-6.86 (m, 3H); 3.72(br. s, 1H); 3.48 (br. s, 1H); 2.09 (br. d, J=8.4, 1H), 1.97 (br. d,J=9.3, 2H); 1.69 (br. d, J=8.7, 1H); 1.27 (br. d, J=9.3, 2H). IR (cm⁻¹,KBr): 3274 (s), 2991 (m), 2957 (m), 1672 (s), 1605 (s), 1525 (s), 1497(s), 1441 (m), 1352 (m), 1273 (s), 1230 (m), 1146 (m), 1126 (m), 1085(m), 966 (m), 889 (m), 851 (m). MS (m/z): 381.0 ([M+H]⁺).

Example 286N(3)-[(2-Chlorophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (114 μl, 0.83 mmol), BOP reagent (152 mg, 0.34 mmol) and2-chlorophenylhydrazine hydrochloride (61 mg, 0.34 mmol) gave the titlecompound (108 mg, 76° M. M.P.: 126-129° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.55 (br. s, 1H); 7.75-7.65 (m, 1H); 7.29 (d, J=7.2, 1H); 7.14 (t,J=8.1, 1H); 7.04 (br. t, J=8.1, 3H); 6.83 (t, J=6.9, 1H); 3.71 (br. s,1H); 3.49 (br. s, 1H); 2.09 (d, J=9.0, 1H); 1.97 (d, J=9.0, 2H); 1.70(d, J=9.0, 1H); 1.26 (br. d, J=8.4, 2H). IR (KBr, cm⁻¹): 3247 (br. m),2956 (m), 2873 (m), 1670 (s), 1595 (m), 1524 (s), 1494 (s), 1439 (m),1349 (m), 1270 (s), 1254 (m), 1141(m), 1048 (m), 1034 (m), 964 (m), 887(w), 848 (m), 750 (s). MS (m/z): 415.10 ([M+H]⁺).

Example 287N(3)-[(2-bromophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed tier example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF(1.0 ml), Et₃N (114 μl, 0.83 mmol), BOP reagent (152 mg, 0.34 mmol) and2-bromophenylhydrazine hydrochloride (76 mg, 0.34 mmol) gave the titlecompound (125 mg, 79%). M.P.: 134-137° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.57 (br. s, 1H); 7.74-7.65 (m, 1H); 7.46 (d, J=7.8, 1H); 7.19 (t,J=7.8, 1H); 7.10-6.90 (m, 3H); 6.77 (t, J=8.1, 1H); 3.72 (br. s, 1H);3.49 (br. s, 1H); 2.12 (br. d, J=8.7, 1H); 1.97 (br. d, J=9.0, 2H); 1.70(br. d, J=8.7, 1H); 1.27 (br. d, J=9.0, 2H). IR (KBr, cm⁻¹): 3327 (s),3295 (m), 2969 (m), 2869 (m), 1656 (s), 1609 (m), 1594 (m),1524 (s),1481 (s), 1449 (m), 1353 (m), 1271 (s), 1.229 (m), 1093 (s), 1071 (m),1046 (m), 1021 (m), 846 (s).

Example 288N(3)-[(2-Fluorophenyl)amino]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (114 μl, 0.83 mmol), BOP reagent (152 mg, 0.34 mmol) and2-fluorophenylhydrazine hydrochloride (55 mg, 0.34 mmol) gave the titlecompound (94 mg, 69%). M.P.: 172-175° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):8.54 (br. s, 1H); 7.71 (dt, J=8.4, 2.4, 1H); 7.10-6.96 (m, 5H);6.90-6.80 (m, 1H); 3.72 (br. s, 1H); 3.49 (br. s, 1H); 2.11 (br. d,J=7.2, 1H); 1.97 (d, J=9.3, 2H); 1.71 (d, J=9.0, 1H); 1.30-1.25 (m, 2H).IR (KBr, cm⁻¹): 3339 (s), 2989 (m), 2871 (m), 1685 (s), 1614 (m), 1.523(s), 1498 (s), 1439 (s), 1271 (m), 1233 (m), 1192 (m), 1143(m), 1061(m), 1027 (m), 966 (m), 862 (m). MS (m/z): 399.10 ([M+H]⁺).

Example 289N(3)-Piperidino-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (58 μl, 0.42 mmol), BOP reagent (166 mg, 0.38 mmol) and1-aminopiperidine (37 μl, 0.34 mmol) gave the title compound (42 mg,33%). M.P.: 143° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.61 (m, 1H);7.58 (br. s, 1H); 7.02 (t, J=8.4, 2H); 3.75 (br. s, 1H); 3.44 (br. s,1H), 2.8.8 (br. s, 4H); 2.09 (br. d, J=8.7, 1H); 2.10-1.90 (m, 2H);1.78-1.65 (m, 5H); 1.50-1.34 (m, 2H); 1.34-1.08 (m, 2H). IR (KBr, cm⁻¹):3263 (m), 2994 (m), 2942 (m), 2872 (m), 2853 (m), 1658 (s), 1611 (m),1521 (s), 1444 (m); 1353 (m), 1269 (s), 1233 (m), 1143 (m), 1121 (m),1089 (m), 965 (m), 907 (m). MS (m/z): 373.2 ([M+H]⁺).

Example 290N(3)-Cyclohexyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.42 mmol), BOP reagent (166 mg, 0.38 mmol) andcyclohexylamine (39 μl, 0.34 mmol) gave the title compound (41 mg, 32%).M.P.: 119° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70-7.60 (m, 1H); 7.01(t, J=7.8, 2H); 6.72 (br. d, J=8.1, 1H); 4.03-3.85 (m, 1H); 3.75 (br. s,1H), 3.44 (br. s, 1H); 2.10-1.95 (m, 5H); 1.80-1.42 (m, 5H); 1.40-1.15(m, 6H). IR (KBr, cm⁻¹): 3294 (m), 2995 (m), 2933 (s), 2853 (m), 1641(s), 1610 (m), 1548 (s), 1520 (s), 1499 (s), 1451 (m), 1352 (m), 1269(m), 1251 (m), 1239 (m), 1160 (m), 1142 (m), 1122 (m), 1090 (m), 964(m), 851 (m). MS (m/z): 372.1 ([M+H]⁺).

Example 291N(3)-(Cyclohexylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.41 mmol), BOP reagent (152 mg, 0.34 mmol) and2-cyclohexylmethyl amine (44 μl, 0.34 mmol) gave the title compound (87mg, 65%). M.P.: 94-97° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.67 (m, 1H);7.01 (t, J=8.1, 2H); 6.91 (br. s, 1H); 3.75 (br. s, 1H); 3.44 (br. s,1H); 3.26 (t, J=6.6, 2H); 2.08 (br. d, J=8.7, 1H); 2.05-1.85 (m, 2H);1.83-1.50 (m, 6H); 1.26-1.18 (m, 6H); 1.05-0.85 (m, 2H). IR (KBr, cm⁻¹):3379 (m), 2926 (s), 2848 (m), 1655 (s), 1556 (m), 1519 (s), 1499 (m),1450 (m), 1271 (m), 1241 (m), 1.142 (m), 1088 (m), 962 (w), 852 (w). MS(m/2): 386.20 ([M+H]⁺).

Example 292N(3)-[S-(1-Phenylethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.41 mmol), BOP reagent (152 mg, 0.34 mmol) andS-(−)-1-phenethylamine (44 μl, 0.34 mmol) gave the title compound (85mg, 63%). M.P.: 54-57° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66 (dt,J=9.0, 5.7, 1H); 7.40-7.20 (m, 5H); 7.11 (br. d, J=7.5, 1H); 7.00 (t,J=8.7, 2H); 5.35-5.28 (m, 1H); 3.74 (br. s, 1H); 3.44 (br. s, 1H); 2.07(br. t, J=8.6, 1H); 1.94 (br. s, 2H); 1.70-1.55 (m, 4H); 1.33-1.25 (m,2H). IR (KBr, cm⁻¹): 3412 (m), 3310 (w), 2971 (m), 2872 (m), 1664 (s),161.1 (m), 1523 (s), 1493 (s), 1447 (s), 1359 (m), 1271 (s), 1232 (m),1180 (m), 1144 (s), 1121 (m), 1091 (m), 965 (an), 850 (n). MS (m/z):394.0 ([M+H]⁺).

Example 293N(3)-(R-1-phenylethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.38 mmol), BOP reagent (152 mg, 0.36 mmol) andR-1-phenylethylamine (44 μl, 0.37 mmol) furnished the title compound (75mg, 56%). M.P.: 40-45° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.60 (m,1H); 7.46-7.19 (m, 5H); 7.15-6.90 (m, 3H); 5.31 (br. s, 1H); 3.74 (br.s, 1H); 3.43 (br. s, 1H); 2.07 (br. s, 1H); 1.95 (br. s, 2H); 1.72-1.51(m, 4H); 1.44-1.17 (m, 2H). IR (cm⁻¹, KBr): 3412 (s), 3062 (m), 3029(m), 2970 (s), 29230 (s), 2872 (m), 1663 (s), 1610 (s), 1523 (s), 1493(s), 1447 (s), 1358 (m), 1326 (m), 1270 (s), 1252 (s), 1232 (s), 1210(m), 1160 (s), 1143 (s), 1121 (s), 1191 (s), 965 (m) 850 (m), 831(m). MS(m/z): 394.2 ([M+H]⁺); 290.2 (100).

Example 294N(3)-(1-Methyl-1-phenylethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.38 mmol), BOP reagent (152 mg, 0.36 mmol) andα,α-dimethylbenzylamine (56 mg, 0.41 mmol) furnished the title compound(80 mg, 58%). M.P.: 105° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.69 (dt,J=9.6, 6.0, 1H); 7.49 (d, J=7.8, 2H); 7.34 (t, J=7.8, 2H); 7.28-7.18 (m,2H); 7.06-6.96 (m, 2H); 3.70 (br. s, 1H); 3.43 (br. s, 1H); 2.06 (br. d,J=8.7, 1H); 2.00-1.86 (m, 2H); 1.66 (br. d, J=8.4, 1H); 1.35-1.17 (m,2H). IR (cm⁻¹, KBr): 3334 (s), 2965 (s), 2929 (s), 2873 (m), 1656 (s),1609 (s), 1522 (s), 1495 (s), 1449 (s), 1385 (m), 1362 (m), 1326 (w),1308 (m), 1271 (s), 1252 (s), 1237 (s), 1194 (m), 1156 (w), 1143 (m),1121 (m), 1106 (m), 1091 (m), 965 (m) 848 (m), 831(m). MS (m/z): 408.1(40, [M+H]⁺); 290.3 (100).

Example 295N5-[1-(2-Chlorophenyl)-1-methylethyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.37 mmol) and2-(2-chlorophenyl)-prop-2-ylamine (87 mg, 0.51 mmol) furnished the titlecompound (87 mg, 57%). M.P.: 176-179° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.75-7.60 (m, 1H); 7.58 (d, J=7.8, 1H); 7.41-7.12 (m, 4H); 7.06-6.95 (m,2H); 3.64 (s, 1H); 3.42 (s, 1H); 2.04 (d, J=8.4, 1H); 1.95-1.85 (m, 8H),1.62 (d, J=9.3, 1H), 1.23 (d, J=9.0, 2H). IR (cm⁻¹, KBr): 3413 (m), 2975(m), 2871 (m), 1675 (s), 1613 (w), 1522 (s), 1491 (m), 1447 (m), 1383(w), 1362 (w), 1270 (s), 1244 (m), 1144 (m), 1091 (w), 1037 (w), 965(w), 853 (w), 755 (w). MS (m/z): 442.1 ([M+H]⁺).

Example 296N(3)-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (120 mg, 0.41 mmol), DMF (1.0ml), Et₃N (137 μl, 0.99 mmol), BOP reagent (182 mg, 0.41 mmol) and 1S,2endo-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylamine hydrochloride (77 mg,0.41 mmol) furnished the title compound (86 mg. 49%). M.P.: 114-117° C.¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 7.86-7.76 (m, 1H), 7.60 (br. t, J=9.3,1H); 7.29 (br. t, J=8.1, 1H); 7.00 (d, J=9.6, 1H); 3.63 (d, J=9.3, 1H);3.52, (br. s, 1H); 3.46 (br. s, 1H); 2.05-1.85 (m, 3H); 1.75-1.55 (m,4H); 1.50-1.35 (m, 2H); 1.25-0.95 (m, 10H); 0.77 (d, J=5.1, 3H). IR(cm⁻, KBr): 3390 (m), 2952 (s), 2873 (m), 1658 (s), 1607 (w), 1520 (s),1496 (s), 1451 (m), 1475 (m), 1368 (w), 1329 (m), 1252 (m), 1232 (m),1158 (m), 1148 (m), 964 (m), 822 (w). MS (m/z): 426.3 ([M+H]⁺).

Example 297N5-(2-Chlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.41 mmol), BOP reagent (167 mg, 0.37 mmol) and2-chlorobenzylamine (41 μl, 0.34 mmol) furnished the title compound (100mg, 68%). M.P.: 102-105° C. ¹H-NMR (δ ppm, DMSO-d₆, 300 MHz): 8.67-8.73(m, 1H), 7.89-7.77 (m, 1H); 7.66-7.57 (m, 1H); 7.44 (d, J=7.2, 1H);7.34-7.30 (m, 4H); 4.49 (br. s, 2H); 3.55 (br. s, 1H); 3.47 (br. s, 1H);2.00-1.92 (m, 3H); 1.66 (d, J=8.7, 1H); 1.17-1.05 (m, 2H). IR (cm⁻¹,KBr): 3337 (m), 2965 (m), 2868 (w), 1657 (m), 1645 (s), 1623 (m), 1526(s), 1271 (m), 1243 (w), 1234 (w), 1160 (m), 846 (m), 738 (w).

Example 298N5-(4-Chlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (50 μl, 0.37 mmol), BOP reagent (159 mg, 0.36 mmol) and4-chloro-benzylamine (63 μl, 0.51 mmol) furnished the title compound (96mg, 67%). M.P.: 121-125° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.67-7.57(m, 1H); 7.30-7.25 (m, 4H); 7.20-7.15 (m, 1H); 7.05-6.95 (m, 2H); 4.57(d, J=4.8, 2H); 3.76 (br. s, 1H); 3.45 (br. s, 1H), 2.09 (d, J=9.0, 1H);2.00-1.93 (m, 2H); 1.69 (d, J=9.0, 1H); 1.28-1.24 (m, 2H). IR (cm⁻¹,KBr): 3310 (m), 2964 (m), 2939 (m), 2874 (m), 1644 (s), 1607 (w), 1557(s), 1520 (s), 1491 (s), 1454 (m), 1407 (w), 1358 (m), 13.26 (w), 1272(m), 1254 (m), 1232 (M), 1160 (m), 1142 (m), 1088 (m), 1013 (m), 962(m), 853 (m). MS (m/z): 412.25 (100%), 414.2 ([M+H]⁺).

Example 299N5-(1-Ethyl-1-phenylpropyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (1.52 mg, 0.34 mmol) andα,α-diethylbenzylamine (72 mg, 0.44 mmol) furnished the title compound(85 mg, 86%). M.P.: 45-48° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.76-7.66(m, 1H), 7.42-7.10 (m, 6H); 7.07-6.96 (m, 2H); 3.70 (br. s, 1H); 3.45(br. s, 1H); 2.23 (q, J=7.2, 4H); 2.06 (d, J=9.0, 1H); 1.93 (d, J=8.4,2H); 1.66 (d, J=8.7, 1H); 1.26 (d, J=5.4, 2H); 0.78 (t, J=7.2, 6H). IR(cm⁻¹, KBr): 3407 (m), 3059 (m), 2968 (s), 2975 (s), 2935 (s), 1.681(s), 1610 (m), 1583 (s), 1524 (s), 1491 (m), 1447 (m), 1377 (w), 1327(w), 1270 (m), 1234 (m), 1144 (m), 1091 (m), 965 (m), 850 (m), 756 (m),698 (m). MS (m/z): 436.0 [M+H]⁺.

Example 300N5-[(1S)-1-Phenylpropyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and(s)-(α)-ethylbenzyl amine (51 mg, 0.37 mmol) furnished the titlecompound (70 mg, 50%). M.P.: 100-103° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.71-7.62 (m, 1H), 7.39-7.25 (m, 5H); 7.23-6.96 (m, 3H); 5.05 (quintet,J=7.8, 1H); 3:72 (br. s, 1H); 3.43 (br. s, 1H); 2.10-1.85 (m, 5H); 1.66(d, J=9.0, 1H); 1.27-1.19 (m, 2H); 1.00-0.92 (m, 3H). IR (cm⁻¹, KBr):3282 (m), 2968 (m), 2874 (m), 1641 (s), 1614 (m), 1522 (s), 1494 (s),1454 (m), 1359 (m), 1269 (m), 1231 (m) 1159 (m), 1140 (m), 1120 (m),1094 (m), 963 (m), 847 (m), 701 (m). MS (m/z): 290 (100%), 408.2 (M+H⁺).

Example 301Methyl(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]-2-phenylethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (510 mg, 1.76 mmol), DMF (4.0ml), Et₃N (580 μl, 4.20 mmol), BOP reagent (777 mg, 1.76 mmol) and(S)-(+)-2-phenylglycine methyl ester hydrochloride (354 mg, 1.76 mmol)furnished the title compound (420 mg, 55%). M.P.: 72-75° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 8.47 (d, J=7.5, 1H), 7.86-7.81 (m, 1H); 7.61 (t,J=8.4, 1H); 7.45-7.29 (m, 6H); 5.65 (d, J=6.9, 1H); 3.66 (s, 3H); 3.52(br. s, 1H); 3.47 (br. s, 1H); 1.94 (br. s, 3H); 1.67 (br. s, 1H);1.25-1.05 (m, 2H); IR (cm⁻¹, KBr): 3412 (m), 2953 (m), 2872 (m), 1745(s), 1674 (s), 1610 (m), 1524 (s), 1488 (s), 1452 (m), 1358 (m), 1328(w), 1295 (w) 1270 (s), 1211 (m), 1160 (m), 1144 (m), 1121 (m), 1092(m), 965 (m), 850 (w), 698 (m). MS (m/z): 438.2 (M+H⁺.

Example 302N5-[(1S)-2-Hydroxy-1-phenylethyl]-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 191. To a solution of Example 301 (290 mg, 0662mmol) in THF (3 ml) was added LiBH₄ (32 mg, 1.52 mmol) and the mixturewas refluxed overnight. After evaporation of the solvent, the oilyresidue was diluted with water and acidified with 1N HCl and extractedwith ethyl acetate and the combined organic layers were washed withbrine and dried over Na₂SO₄. FC (3:7 AcOEt/petroleum ether) gave thetitle compound (170 mg, 63%). M.P.: 91° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.71-7.61 (m, 1H); 7.46-7.29 (m, 6H); 7.00 (t, J=8.4, 2H); 5.23(br. q, J=5.1, 1H), 3.98 (br. s, 2H); 3.73 (br. s, 1H); 3.44 (br. s,1H); 2.92 (br. s, 1H); 2.14-1.93 (m, 3H); 1.69 (d, J=8.7, 1H); 1.32-1.24(m, 2H). MS (m/z): 410.1 (M+H⁺).

Example 303N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide[N5-(tert-butyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide]

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.40 mmol), BOP reagent (165 mg, 0.37 mmol) and2-amino-2-methylpropane (36 μl, 0.34 mmol) furnished the title compound(31 mg, 26%). M.P.: 109-111° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.71-7.62 (m, 1H), 7.04-6.97 (m, 2H); 6.74 (br. s, 1H); 3.75 (br. s,1H); 3.43 (br. s, 1H); 2.10-2.04 (m, 1H); 2.01-1.90 (m, 2H); 1.67 (d,J=8.4, 1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H). IR (cm⁻¹, KBr): 3323 (m),2968 (m), 1652 (s), 1609 (s), 1547 (s), 1522 (s), 1495 (w), 1448 (m),1391 (w), 1360 (m), 1272 (m) 1258 (w), 1145 (w), 1109 (m), 965 (m), 849(m). MS (m/z): 346.0 (M+H⁺).

Example 304 & Example 305 (4R,7S) and(4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

Preparation I: The title compound was synthesized by a procedure similarto that described for example 101. Intermediate 21a (late elutingenantiomer, 100 mg, 0.34 mmol), DMF (1.0 ml), Et₃N (57 μl, 0.41 mmol),BOP reagent (167 mg, 0.37 mmol) and 2-amino-2-methylpropane (36 0.34mmol) furnished the title compound (91 mg, 76%). HPLC: R_(t) (CHIRALCELOD-H column, dimensions: 250×4.6 mm, particle size: 5μ, eluent: 0.2%isopropanol in n-hexane, flow rate: 1 ml/min.)=26.59 min.; e.e=92.3%.M.P.: 89-92° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.60 (m, 1H),7.04-6.96 (m, 2H); 6.74 (br. s, 1H); 3.75 (br. s, 1H); 3.43 (br. s, 1H);2.07 (d, J=8.1, 1H); 2.01-1.90 (m, 2H); 1.67 (d, J=8.7, 1H); 1.46 (s,9H); 1.33-1.19 (m, 2H).

Preparation II: The title compound was synthesized by a proceduresimilar to that described for example 101. Intermediate 21b (fasteluting enantiomer, 70 mg, 0.24 mmol), DMF (1.0 ml), Et₃N (38 μl, 0.28mmol), BOP reagent (118 mg, 0.26 mmol) and 2-amino-2-methylpropane (25pd, 0.24 mmol) furnished the title compound (63 mg, 75%). HPLC: R_(t)(CHIRALCEL OD-H column, dimensions: 250×4.6 mm, particle size: 5μ,eluent: 0.2% isopropanol in n-hexane, flow rate: 1 ml/min.)=24.73 min.;e.e.: 90%. M.P.: 89-90° C. Example 305 was cryptochiral at 25° C. inchloroform (C=0.5). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.62 (m, 1H),7.00 (t, J=10.8, 2H); 6.74 (br. s, 1H); 3.75 (br. s, 1H); 3.43 (br. s,1H); 2.07 (d, J=8.4, 1H); 2.01-1.89 (m, 2H); 1.67 (d, J=8.1, 1H); 1.46(s, 9H); 1.33-1.19 (m, 2H).

Example 306N5-n-Pentyl-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg 0.34 mmol) andn-pentylamine (32 mg, 0.37 mmol) furnished the title compound (50 mg,40%). M.P.: 75-78° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70-7.61 (m, 1H),7.01 (t, J=8.4, 2H), 6.83 (br. s, 1H); 3.75 (br. s, 1H); 3.43-3.36 (m,3H); 2.08 (d, J=8.7, 1H), 2.02-1.89 (m, 2H), 1.68 (d, J=8.7, 1H),1.62-1.56 (m, 2H); 1.38-1.24 (m, 6H); 0.94 (t, J=7.2, 3H). IR (cm⁻¹,KBr): 3338 (m), 2960 (m), 2932 (m), 2872 (m), 2857 (m), 1648 (s), 1607(w), 1552 (s), 1453 (s), 151.9 (m), 1356 (m), 1251 (m), 1235 (m) 1159(m), 1142 (m), 1112 (w), 1144 (m), 1087 (m), 1013 (m),853 (m), 624 (m).MS (m/z): 360.1 (M+H⁺).

Example 307N5-(2,4-Dichlorobenzyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and2,4-dichlorobenzylamine (66 mg, 0.34 mmol) furnished the title compound(110 mg, 71%). M.P.: 105-108° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.69-7.60 (m, 1H), 7.44 (d, J=7.8, 1H); 7.39 (d, J=1.8, 2H); 7.29-7.19(m, 2H); 7.00 (t, J=8.1, 2H), 4.65 (d, J=6.3, 2H); 3.74 (br. s, 1H);3.45 (br. s, 1H), 2.08 (d, J=8.4, 1H); 1.98-1.93 (m, 2H); 1.68 (d,J=8.4, 1H); 1.56 (d, J=8.4, 2H). IR (cm¹, KBr): 3394 (m), 2973 (m), 2933(m), 2871 (m), 1660 (s), 1607 (w), 1551 (w), 1587 (m), 1519 (s), 1493(m), 1350 (m), 1326 (w), 1270 (m) 1231 (m), 1162 (m), 1142 (m), 1125(m), 1091 (m), 1050 (m), 985 (w), 961 (m), 856 (m), 824 (m). MS (m/z):448.1 (M+H⁺).

Example 308N5-(1-phenylcyclopropyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) andα,α-cyclopropylbenzylamine (59 mg, 0.44 mmol) furnished the titlecompound (55 mg, 40%). M.P.: 90° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.72-7.61 (m, 1H), 7.51 (br. s, 1H); 7.35-7.14 (m, 5H); 7.06-6.96 (m,2H); 3.73 (br. s, 1H); 3.44 (br. s, 1H); 2.06 (d, J=8.7, 1H); 2.00-1.92(m, 2H); 1.67 (d, J=8.7, 1H); 1.43-1.23 (m, 6H). IR (cm⁻¹, KBr): 3407(w), 3296 (m), 3088 (w), 3056 (w), 2953 (m), 1660 (s), 1607 (m), 1522(s), 1491 (m), 1453 (m), 1355 (m), 1322 (w), 1270 (m), 1230 (m), 1158(m), 1142 (m), 1089 (m), 965 (m), 851 (w). MS (m/z): 406.1 [M+H]⁺.

Example 309N5-(2-Adamantyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and2-adamantanamine hydrochloride (71 mg, 0.37 mmol) furnished the titlecompound (123 mg, 84%). M.P.: 159-161° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.74-7.64 (m, 1H), 7.21 (d, J=7.8, 1H), 7.05-6.95 (m, 2H); 4.23(d, J=8.4, 1H); 3.73 (br. s, 1H); 3.44 (br. s, 1H); 2.10-1.79 (m, 13H);1.77-1.55 (m, 7H). IR (cm⁻¹, KBr): 3414 (m), 2909 (s), 2855 (m), 1659(s), 1614 (w), 1603 (w), 1545 (s), 1530 (s), 1494 (m), 1470 (w), 1448(w), 1346 (w) 1290 (s), 1272 (m), 1226 (m), 1154 (m), 1122 (m), 967 (m),869 (m). MS (m/z): 424.3 (M+H⁺).

Example 310N5-(2-Methyl-2-adamantyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and2-methyl-2-adamantylamine (73 mg, 0.44 mmol) furnished the titlecompound (110 mg, 73%). M.P.: 60° C. ¹H-NMR, □ ppm, CDCl₃, 300 MHz):7.71-7.63 (m, 1H), 7.02-6.95 (m, 2H); 6.82 (br. s, 1H); 3.74 (br. s,1H); 3.44 (br. s, 1H); 2.30 (br. s, 2H); 2.04-1.79 (m, 9H); 1.73-1.62(m, 10H); 1.25 (s, 3H). IR (cm⁻¹, KBr): 3406 (m), 2920 (s), 2861 (s),1672 (s), 1610 (m), 1543 (s), 1524 (s), 1493 (s), 1446 (s), 1377 (w),1368 (w), 1353 (m), 1270 (s), 1256 (m), 1227 (m), 1161 (m), 1144 (m),1105 (m),965 (m),849 (m), 815 (w), 578(m). MS (m/z): 438.1.

Example 311N7-(3-Hydroxyadamantan-1-yl)-5-(2,4-difluorophenyl)-5,6-diazatetracyclo[7.3.1.1^(3,11).0^(4,8)]tetradeca-4(8),6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (200 mg, 0.68 mmol), DMF (2.0ml), Et₃N (110 μl, 0.82 mmol), BOP reagent (335 mg, 0.75 mmol) and3-amino-1-adamantanol (115 mg, 0.68 mmol) furnished the title compound(185 mg, 55%). M.P.: 180-182° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.70-7.61 (m, 1H); 7.04-6.96 (m, 2H); 6.69 (br. s, 1H); 3.72 (br. s,1H); 3.43 (br. s, 1H), 2.30 (br. s, 2H); 2.13 (br. s, 2H); 2.10-1.94 (m,7H); 1.73-1.51 (m, 8H); 1.33-1.19 (m, 2H). IR (cm⁻¹, KBr): 3418 (s),3369 (s), 2913 (s), 2885 (s), 1651 (s), 1610 (m), 1548 (s), 1519 (s),1495 (s), 1455 (m), 1421 (w), 1359 (m), 1341 (w), 1314 (m), 1270 (s),1233 (s), 1145 (m), 1115 (m), 1102 (m), 1049 (w), 1032 (w), 965 (m), 846(m). MS (m/z): 440.1 ([M+H]⁺).

Example 3124-[5-(2,4-Difluorophenyl)-4,5-diazatricyclo[5.1.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]morpholine

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (53 μl, 0.37 mmol), BOP reagent (159 mg, 0.36 mmol) and4-morpholinamine (115 mg, 0.68 mmol) furnished the title compound (100mg, 78%). M.P.: 106-110° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70-7.61(m, 2H); 7.06-6.98 (m, 2H); 3.85 (t, J=4.5, 4H); 3.74 (br. s, 1H); 3.44(br. s, 1H); 2.96 (t, J=4.5, 4H); 2.08 (d, J=8.7, 113); 1.97-1.94 (m,2H); 1.69 (d, J=9.0, 1H); 1.27-1.23 (m, 2H). IR (cm⁻¹, KBr): 3435 (m),3262 (m), 3085 (w), 2954 (m), 2925 (m), 2870 (m), 1670 (s), 1614 (m),1523 (s), 1498 (m), 1450 (m), 1387 (w), 1357 (m), 1326 (w), 1269 (s),1232 (s), 1145 (m), 1108 (m), 1093 (m), 1002 (m), 966 (m), 847 (m). MS(m/z): 375.2 ([M+H]⁺).

Example 313N(3)-(tert-Pentyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (53 μl, 0.37 mmol), BOP reagent (159 mg, 0.36 mmol) andtert-amyl amine (60 0.52 mmol) furnished the title compound (109 mg,88%). M.P.: 78-80° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.71-7.61 (m, 1H);7.04-7.02 (m, 2H); 6.66 (br. s, 1H); 3.74 (br. s, 1H); 3.43 (br. s, 1H),2.07 (d, J=8.4, 1H); 1.98-1.78 (m, 4H); 1.67 (d, J=9.0, 1H); 1.41 (s,6H); 1.26-1.20 (m, 2H); 0.91 (t, J=7.2, 3H). MS (m/z): 360.2 ([M+H]⁺).

Example 314N(3)-Cyclopropanmethyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (116 μl, 0.83 mmol), BOP reagent (159 mg, 0.36 mmol) and aminomethyl cyclopropane hydrochloride (55 mg, 0.51 mmol) furnished the titlecompound (101 mg, 85%). M.P.: 113-115° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.72-7.62 (m, 1H); 7.06-6.92 (m, 3H); 3.75 (br. s, 1H); 3.44 (br.s, 1H), 3.28 (t, J=5.7, 2H); 2.08 (d, 7.8, 1H); 1.96 (br. s, 2H); 1.68(d, J=9.3, 1H); 1.26 (br. s, 2H); 1.06-1.02 (m, 1H); 0.52 (d, J=7.5,2H); 0.26 (d, J=4.2, 2H). MS (m/z): 344.1 ([M+H]⁺).

Example 315N(3)-Cyclobutyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (116 μl, 0.83 mmol), BOP reagent (160 mg, 0.36 mmol) andcyclobutyl amine hydrochloride (115 mg, 0.68 mmol) furnished the titlecompound (92 mg, 77%). M.P.: 123-125° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.70-7.62 (m, 1H); 7.06-6.96 (m, 3H); 4.56 (quintet, J=7.5, 1H); 3.74(br. s, 1H); 3.43 (br. s, 1H), 2.46-2.36 (m, 2H); 2.07 (d, J=7.8, 1H),2.04-1.95 (m, 5H); 1.78-1.60 (m, 2H); 1.25 (br. s, 2H). MS (m/z): 344.2([M+H]⁺).

Example 316N(3)-(Tetrahydro-2H-4-pyranmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (160 mg, 0.36 mmol) andtetrahydro-2H-4-pyranylmethylamine (60 mg, 0.51 mmol) furnished thetitle compound (103 mg, 77%). M.P.: 107-109° C. ¹H-NMR (δ ppm, CDCl₃,300 MHz): 7.70-7.60 (m, 1H); 7.05-6.96 (m, 3H); 4.10-3.94 (m, 2H); 3.75(br. s, 1H); 3.46-3.2.9 (m, 5H), 2.12-2.02 (m, 1H); 2.00-1.62 (m, 5H);1.44-1.20 (m, 5H). MS (m/z): 386.0 ([M+H]⁺).

Example 317N(3)-Cyclopropyl-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (160 mg, 0.36 mmol) andcyclopropylamine (36 μl, 0.51 mmol) furnished the title compound (103mg, 86%). M.P.: 59-61° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.70-7.62 (m,1H); 7.00 (t, J=9.9, 2H); 6.90 (br. s, 3.75 (br. s, 1H); 3.43 (br. s,1H), 2.88-2.84 (m, 1H); 2.07 (d, J=8.7, 1H); 2.02-1.90 (m, 2H); 1.68 (d,J=8.7, 1H); 1.32-1.15 (m, 2H); 0.82 (d, J=5.1, 2H); 0.62 (br. s, 2H). MS(m/z): 328.0 ([M+H]⁺).

Example 318N(3)-(4-methylpiperazino)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (165 mg, 0.37 mmol) andN-amino-N-methyl piperazine (61 μl, 0.51 mmol) furnished the titlecompound (97 mg, 72%). M.P.: 154-156° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.70-7.62 (m, 1H); 7.58 (br. s, 1H); 7.08-6.96 (m, 2H); 3.74 (br. s,1H); 3.44 (br. s, 1H); 3.03 (br. s, 4H); 2.76 (br. s, 4H); 2.41 (s, 3H);2.08 (d, J=9.3, 1H); 2.00-1.94 (m, 2H); 1.68 (d, J=8.1, 1H); 1.30-1.24(m, 2H).

Example 319 Methyl(2R)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-diene-3-ylcarboxamido]-2-phenylethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (300 mg, 1.03 mmol), DMF (3.0ml), Et₃N (343 μl, 2.48 mmol), BOP reagent (502 mg, 1.13 mmol) andR-(−)-2-phenylglycinmethylester hydrochloride (208 mg, 1.03 mmol)furnished the title compound (334 mg, 74%). M.P.: 61-63° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.78-7.64 (m, 2H); 7.45 (d, J=7.8, 2H); 7.40-7.31(m, 3H); 7.04-6.95 (m, 2H); 5.76 (dd, J=2.1, 7.2, 1H); 3.76 (2s, 3H);3.71 (br. S, 1H); 3.44 (br. S, 1H); 2.11-2.01 (m, 1H); 1.99-1.90 (m,2H); 1.66 (d, J=8.7, 1H); 1.30-1.21 (m, 2H). IR (cm⁻¹, KBr): 3411 (m),3065 (w), 2953 (m), 2872 (w), 1744 (s), 1672 (s), 1610 (m), 1541 (s),1523 (s), 1489 (s), 1454 (m), 1358 (m), 1328 (w), 1295 (w), 1271 (s),1213 (m), 1160 (m), 1145 (m), 1122 (m), 1093 (w), 966 (m), 851 (m). MS(m/z): 480.24 ([M+H]⁺).

Example 320N(3)-[(1R)-2-Hydroxy-1-phenylethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 191. Example 319 (235 mg, 0.54 mmol), TI-IF (4 ml)and LiBH₄ (24 mg, 1.09 mmol) furnished the title compound (153 mg, 69%).M.P.: 68-70° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.25 (d, J=9.0, 1H);7.87-7.82 (m, 1H); 7.63-7.58 (m, 1H); 7.36-7.22 (m, 6H); 5.05-4.94 (m,2H), 3.73-3.67 (m, 2H); 3.50 (br. s, 1H); 3.45 (br. s, 1H); 2.05-1.84(m, 3H); 1.70-1.62 (m, 1H); 1.24-1.20 (m, 2H). MS (m/z): 452.17 (M+H⁺).

Example 321N(3)-(tert-Butyl)-1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 16 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (52 μl, 0.38 mmol), BOP reagent (157 mg, 0.35 mmol) and2-amino-2-methylpropane (53 0.51 mmol) furnished the title compound (56mg, 47%). M.P.: 170-173° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.62 (d,J=8.7, 2H); 7.43 (d, J=8.7, 2H); 6.78 (br. s, 1H); 3.75 (br. s, 1H);3.65 (br. s, 1H); 2.08-1.99 (m, 1H); 2.02-1.94 (m, 2H); 1.70 (d, J=8.4,1H); 1.47 (s, 9H); 1.28-0.99 (m, 2H).

Example 322N(3)-(Tetrahydro-2-furanylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (54 μl, 0.37 mmol), BOP reagent (160 mg, 0.36 mmol) andtetrahydro-2-furanylmethylamine (54 μl, 0.51 mmol) furnished the titlecompound (82 mg, 64%). M.P.: 91-93° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.74-7.62 (m, 1H); 7.15 (br. s, 1H); 7.08-6.94 (m, 2H); 4.12-4.00 (m,1H); 3.94-3.86 (m, 1H); 3.80-3.68 (m, 3H); 3.50-3.30 (m, 2H), 2.10-1.85(m, 6H); 1.72-1.58 (m, 1H); 1.25 (br. s, 3H). MS (m/z): 374.2 ([M+H]⁺).

Example 323N(3)-(tert-Butyl)-1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 20 (100 mg, 0.36 mmol), DMF (1.0ml), Et₃N (54 μl, 0.40 mmol), BOP reagent (170 g, 0.38 mmol) andt-butylamine (57 μl, 0.55 mmol) furnished the title compound (102 mg,85%). M.P.: 131-133° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66-7.60 (m,2H); 7.20-7.12 (m, 2H); 6.78 (br. s, 1H); 3.76 (br. s, 1H); 3.63 (br. s,1H); 2.15-2.10 (m, 1H); 2.00-1.92 (m, 2H); 1.74-1.68 (m, 1H); 1.47 (s,9H); 1.30-1.16 (m, 2H). MS (m/z): 328.15 ([M+H]⁺),

Example 324N(3)-(tert-Butyl)-1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 19 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (45 μl, 0.33 mmol), BOP reagent (139 mg, 0.31 mmol) and2-amino-2-methylpropane (47 μl, 0.45 mmol) furnished the title compound(87 mg, 75%). M.P.: 157-159° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.57 (s,4H); 6.78 (br. s, 1H); 3.75 (br. s, 1H); 3.65 (br. s, 1H); 2.18-2.07 (m,1H); 2.02-1.92 (m, 2H); 1.70 (d, J=9.0, 1H); 1.47 (s, 9H); 1.28-0.99 (m,2H).

Example 325N(3)-(tert-Butyl)-1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 29 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (47 μl, 0.34 mmol), BOP reagent (143 mg, 0.32 mmol) and2-amino-2-methylpropane (48 μl, 0.46 mmol) furnished the title compound(77 mg, 66%). 205-207° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.83 (s, 1H);7.52 (s, 2H); 6.77 (br. s. 1H); 3.75 (br. s, 1H); 3.67 (br. s, 1H); 2.11(d, J=8.7, 1H); 1.99 (d, 6.3, 2H); 1.71 (d, H=8.7, 1H); 1.48 (s, 9H);1.28-1.16 (m, 2H).

Example 326 Methyl(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]-2-(4-fluorophenyl)ethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (400 mg, 1.37 mmol), DMF (4.0ml), Et₃N (450 μl, 3.31 mmol), BOP reagent (670 mg, 1.51 mmol) and(S)-(−)-2-(4-fluorophenyl)glycine methyl ester hydrochloride (302 mg,1.37 mmol) furnished the title compound (543 mg, 86%). M.P.: 51-52° C.¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.78-7.68 (m, 2H): 7.44-7.41 (m, 2H);7.06-6.95 (m, 4H); 5.63 (d, J=6.9, 1H); 3.77, 3.76 (2s, 3H); 3.70 (brs,1H); 3.44 (br. s, 1H); 2.10-2.02 (m, 1H); 2.00-1.90 (m, 2H); 1.67 (d,J=7.8, 1H); 1.30-1.19 (m, 2H).

Example 327N(3)-(tert-Butyl)-1-(2,4-dichlorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (48 μl, 0.34 mmol), BOP reagent (144 mg, 0.32 mmol) and2-amino-2-methylpropane (48 μl, 0.46 mmol) furnished the title compound(90 mg, 77%). 129-131° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.55 (d,J=2.4, 1H); 7.45 (d, J=8.4, 1H); 7.37 (dd, J=8.4, 2.1, 1H); 6.71 (br. s,1H); 3.76 (br. s, 1H); 3.34 (br. s, 1H); 2.11 (d, J=9.0, 1H); 2.02-1.82(m, 2H); 1.68 (d, J=8.7, 1H); 1.45 (s, 9H); 1.33-1.12 (m, 2H).

Example 328N(3)-(4-Hydroxyphenyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (51 μl, 0.37 mmol), BOP reagent (160 mg, 0.36 mmol) and4-amino-phenol (56 mg, 0.51 mmol) furnished the title compound (112 mg,85%). M.P.: 189-191° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.56 (br. s,1H); 7.75-7.64 (m, 1H); 7.52 (d, J=9.3, 2H); 7.08-6.99 (m, 2H); 6.82 (d,J=8.7, 2H); 5.30 (br. s, 1H); 3.79 (br. s, 1H); 3.47 (br. s, 1H); 2.11(d, J=8.7, 1H); 2.00-1.94 (m, 2H); 1.71 (d, J=8.7, 1H); 1.32-1.22 (m,2H).

Example 329N(3)-tert-Butyl)-1-(2-ethoxy,4-fluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 30 (100 mg, 0.31 mmol), DMF (1.0ml), Et₃N (50 μl, 0.34 mmol), BOP reagent (146 mg, 0.33 mmol) and2-amino-2-methylpropane (40 μl, 0.37 mmol) furnished the title compound(96 mg, 82%). M.P.: 117-120° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.54-7.44 (m, 1H), 6.82-6.69 (m, 3H); 4.12-4.00 (m, 2H); 3.73 (br. s,1H); 3.31 (br. s, 1H); 2.06 (d, J=8.1, 1H); 1.98-1.82 (m, 2H); 1.65 (d,J=8.4, 1H); 1.45 (s, 9H); 1.38 (t, J=6.9, 3H); 1.28-1.20 (m, 2H).

Example 330N(3)-(2-furylmethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.41 mmol), BOP reagent (167 mg, 0.37 mmol) andfurfurylamine (38 μl, 0.41 mmol) furnished the title compound (98 mg,77%). M.P.: 99-100° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.71-7.61 (m,1H); 7.36 (br. s, 1H); 7.19-7.11 (m, 1H); 7.00 (t, J=8.4, 2H); 6.30 (d,J=7.5, 2H); 4.60 (d, J=5.1, 2H); 3.76 (br. s, 1H); 3.44 (br. s, 1H);2.08 (d, J=7.5, 1H); 2.02-1.90 (m, 2H), 1.68 (d, J=8.1, 1H); 1.32-1.22(m, 2H).

Example 331N(3)-(2-thiophenemethyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (57 μl, 0.37 mmol), BOP reagent (167 mg, 0.37 mmol) and2-thiophene methylamine (42 μl, 0.41 mmol) furnished the title compound(106 mg, 80%). M.P.: 103-105° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.70-7.58 (m, 1H); 7.24-7.12 (m, 2H); 7.05-6.94 (m, 4H); 4.78 (d, J=4.5,2H); 3.77 (br. s, 1H); 3.44 (br. s, 1H); 2.08 (d, J=6.3, 1H); 2.02-1.89(m, 2H), 1.69 (d, J=9.0, 1H); 1.34-1.20 (m, 2H).

Example 332N(3)-[(1S)-2-Hydroxy-1)-(4-fluorophenyl)ethyl]-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 191. Example 326 (400 mg, 0.87 mmol), THF (6 ml)and LiBH4 (38 mg, 1.75 mmol) furnished the title compound (288 mg, 76%).M.P.: 116-119° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.65 (q, J=8.4, 1H);7.49-7.41 (m, 1H); 7.40-7.32 (m, 2H); 7.08-6.96 (m, 4H); 5.24-5.18 (m,1H), 3.96 (d, J=5.1, 2H); 3.72 (br. s, 1H); 3.44 (br. s, 1H); 2.12-2.02(m, 2H); 1.99-1.92 (m, 2H); 1.68 (d, J=8.7, 1H); 1.28-1.20 (m, 2H).

Example 333Methyl-(2S)-2-[5-(2,4-difluorophenyl)-4,5-diazatricyclo[5.2.1.0^(2,6)]deca-2(6),3-dien-3-ylcarboxamido]-4-methylpentanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (104 μl, 0.74 mmol), BOP reagent (159 mg, 0.37 mmol) andL-leucine methyl ester hydrochloride (75 mg, 0.50 mmol) furnished thetitle compound (87 mg, 60%) as a waxy solid. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.78-7.65 (m, 1H); 7.21-7.10 (m, 1H); 7.12-6.95 (m, 2H); 4.90-4.75(m, 1H); 3.75 (s, 4H); 3.45 (br. s, 1H); 2.12-2.02 (m, 1H); 2.00-1.90(m, 2H); 1.80-1.60 (m, 6H); 1.34-1.18 (m, 2H), 1.02-0.90 (m, 4H).

Example 334N(3)-(Adamantan-1yl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0ml), Et₃N (50 μl, 0.37 mmol), BOP reagent (159 mg, 0.36 mmol) and1-adamantyl amine (78 mg, 0.51 mmol) furnished the title compound (88mg, 60%). M.P.: 146-148° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.60(m, 1H); 7.04-6.94 (m, 2H); 6.61 (br. s, 1H); 3.73 (br. s. 1H); 3.42(br. s, 1H); 2.20-2.03 (m, 10H); 1.98-1.92 (m, 2H); 1.80-1.52 (m, 4H);1.44-1.19 (m, 5H).

Example 335aN(3)-(tert-butyl)-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 32a (100 mg, 0.34 mmol), DMF(1.0 ml), Et₃N (55 μl, 0.39 mmol), BOP reagent (162 mg, 0.36 mmol) and2-amino-2-methylpropane (44 μl, 0.41 mmol) furnished the title compound(85 mg, 71%) as an oil. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.24-7.14 (m,2H); 7.04 (t, J=8.4, 2H); 6.67 (br. s, 1H); 5.18 (s, 2H); 3.64 (br. s,1H); 3.03 (br. s, 1H); 1.98-1.65 (m, 3H), 1.55 (d, J=8.7, 1H); 1.45 (s,9H); 1.18-1.08 (m, 1H); 0.86-0.74 (m, 1H).

Example 335bN(3)-(tert-butyl)-2-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 32b (50 mg, 0.17 mmol), DMF (1.0ml), Et₃N (30 μl, 0.19 mmol), BOP reagent (80 mg, 0.18 mmol) and2-amino-2-methylpropane (20 μl, 0.19 mmol) furnished the title compound(40 mg, 67%). M.P.: 130-134° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.30-7.20 (m, 2H); 6.94 (t, J=8.7, 2H); 5.80 (d, J=14.7, 1H); 5.72 (br.s, 1H); 5.43 (d, J=14.4, 1H); 3.40 (br. s, 1H); 3.29 (br. s, 1H),1.98-1.88 (m, 3H); 1.68 (d, J=8.4, 1H); 1.42 (s, 9H); 1.21 (d, J=9.6,2H).

Example 336aN(3)-(tert-butyl)-1-(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 31a (100 mg, 0.35 mmol), DMF(1.0 ml), Et₃N (55 μl, 0.39 mmol), BOP reagent (164 mg, 0.37 mmol) and2-amino-2-methylpropane (56 μl, 0.53 mmol) furnished the title compound(71 mg, 65%). ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.16 (d, J=8.1, 2H); 7.10(d, J=8.1, 2H); 6.69 (br. s, 1H); 5.17 (s, 2H); 3.63 (br. s, 1H); 2.99(br. s, 1H); 2.34 (s, 3H), 1.94-1.78 (m, 2H); 1.72-1.64 (m, 1H); 1.53(d, J=8.7, 1H); 1.45 (s, 9H); 1.18-1.08 (m, 1H); 0.90-0.78 (m, 1H).

Example 336bN(3)-(tert-butyl)-2(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 32b (68 mg, 0.24 mmol), DMF (1.0ml), Et₃N (38 μl, 0.26 mmol), BOP reagent (111 mg, 0.25 mmol) and2-amino-2-methylpropane (38 μl, 0.41 mmol) furnished the title compound(44 mg, 54%). M.P.: 142-1.44° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.18(d, J=7.8, 2H); 7.07 (d, J=7.8, 2H); 5.80 (d, J=14.7, 1H); 5.71 (br. s,1H); 5.41 (d, J=14.7, 1H); 3.39 (br. s, 1H); 3.28 (br. s, 1H); 2.28 (s,3H); 1.98-1.89 (m, 3H); 1.70-1.62 (m, 1H); 1.42 (s, 9H), 1.20 (d, J=9.0,2H).

Example 401N(3)-Phenyl-1-(2,4-dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (43 μl, 0.30 mmol), BOP reagent (127 mg, 0.29 mmol) andaniline (28 μl, 0.30 mmol) furnished the title compound (85 mg, 71%).M.P.: 112-115° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.64 (br. s, 1H); 7.67(d, J=7.8, 2H); 7.59 (br. s, 1H); 7.47-7.25 (m, 4H); 7.09 (t, J=7.5,1H); 3.29 (d, J=3.6, 1H); 2.22-2.08 (m, 1H); 1.83 (br. t, J=9.3, 1H);1.43-1.20 (m, 2H); 0.93 (s, 6H); 0.85 (s, 3H). IR (cm⁻¹, KBr): 3274 (s),3251 (s), 2955 (m), 2928 (s), 2869 (m), 1663 (s), 1517 (s), 1546 (s),1533 (m), 1596 (s), 1502 (s), 1474 (m), 1436 (s), 1388 (m), 1345 (m),1323 (s), 1252 (m), 1220 (m), 1229 (m), 1129 (m), 1117 (m), 1102 (m),1077 (m), 1062 (s), 1014 (m), 1001 (m). MS (m/z): 440.3 ([M+H]⁺).

Example 402N(3)-[2-Fluorophenyl)amino]-1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (43 μl, 0.30 mmol), BOP reagent (127 mg, 0.29 mmol) and2-fluorophenyl hydrazine (49 mg, 0.30 mmol) to give the title compound(85 mg, 83%). M.P.: 72-80° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.54 (br.s, 1H); 7.60 (br. s, 1H); 7.42 (d, J=8.4, 1H); 7.38 (d, J=8.7, 1H);7.14-6.95 (m, 3H); 6.87-6.78 (m, 1H); 3.21 (d, J=3.3, 1H); 2.20-2.06 (m,1H); 1.82 (br. t, J=9.0, 1H); 1.41-1.18 (m, 2H); 0.93 (s, 3H); 0.91 (s,3H); 0.82 (s, 3H): IR (cm⁻¹, KBr): 3413 (m), 2912 (s), 2845 (m), 1667(s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162(m), 1103 (m), 1088 (m), 996 (m), 866 (w). MS (m/z): 473.10 ([M+H]⁺).

Example 403N(3)-[(2,4-fluorophenyl)amino]-1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (127 mg, 0.29 mmol) and3,5-difluorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) gave thetitle compound (90 mg, 67%). M.P.: 145-148° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.78 (br. s, 1H); 7.60 (d, J=1.8, 1H); 7.45-7.35 (m, 2H);7.10-6.98 (m, 1H); 6.86-6.70 (m, 2H); 3.22 (d, J=3.6, 1H); 2.20-2.05 (m,1H); 1.88-1.80 (m, 1H); 1.40-1.20 (m, 2H); 0.93, 0.88, 0.82 (3s, 9H). IR(cm⁻¹, KBr): 3339 (m), 3269 (m), 2979 (m), 2961 (m), 1678 (s), 1508 (s),1472 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). MS (m/z):491.10 ([M+H]⁺).

Example 404N(3)-[(3-chloropyridin-2-yl)amino]-1-(2,4-Dichlorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0ml), Et₃N (43 μl, 0.31 mmol), BOP reagent (127 mg, 0.29 mmol) and3-chloro-2-hydrazinopyridine (45 mg, 0.31 mmol) to give the titlecompound (75 mg, 56%). M.P.: 142-145° C. ¹H-NMR (3 ppm, DMSO-d₆, 300MHz): 9.88 (br. s, 1H); 8.42 (br. s, 1H); 8.00 (d, J=9.6, 2H); 7.30-7.55(m, 3H); 6.75 (br. s, 1H); 3.05 (br. s, 1H); 2.09 (br. s, 1H); 1.80 (br.s, 1H); 1.40-1.05 (m, 2H); 0.88, 0.86, 0.80 (3s, 9H). IR (cm⁻¹, KBr):3339 (m), 3269 (m), 2961 (m), 2979 (m), 1678 (s), 1508 (s), 1472 (m),1437 (m), 1312 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m). MS(m/z): 490.00 ([M+H]⁺).

Example 405N(3)-(Adamantan-1-yl)-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0ml), Et₃N (60 μl, 0.43 mmol), BOP reagent (159 mg, 0.36 mmol) and1-adamantylamine (54 mg, 0.36 mmol) furnished the title compound (120mg, 71%). M.P.: 162-165° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.50-7.40(m, 1H); 7.03-6.93 (m, 2H); 6.59 (s, 1H); 3.21 (d, J=3.6, 1H); 2.13-2.07(m, 9H); 1.84-1.63 (m, 7H); 1.37-1.24 (m, 3H); 0.97 (s, 3H); 0.90 (s,3H); 0.77 (s, 3H). IR (cm⁻¹, KBr): 3299 (m), 2958 (m), 2910 (s), 1652(s), 1614 (m), 1605 (m), 1548 (s), 1524 (s), 1499 (s), 1454 (m), 1358(m), 1324 (w), 1269 (m), 1224 (s), 1202 (m), 1143 (m), 1121 (w), 1017(w), 981 (w), 945 (w), 847 (m). MS (m/z): 466.2 ([M+H]⁺).

Example 406N(3)-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0ml), Et₃N (120 μl, 0.86 mmol), BOP reagent (159 mg, 0.36 mmol) and1S,2endo-1,3,3-trimethyl-bicyclo[2.2.1]hept-2-*mine hydrochloride (68mg, 0.36 mmol) furnished the title compound (95 mg, 57%). M.P.:1.71-173° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.56-7.45 (m, 1H),7.05-6.90 (m, 2H); 6.89 (d, J=9.0, 1H); 3.76 (d, J=9.0, 1H); 3.22 (t,J=3.9, 1H); 2.19-2.06 (m, 1H); 1.86-1.62 (m, 4H); 1.54-0.74 (m, 24H). IR(cm⁻¹, KBr): 3419 (m), 2954 (s), 2871 (s), 1672 (s), 1612 (m), 1542 (s),1521 (s), 1493 (s), 1388 (m), 1328 (w), 1318 (w), 1220 (m), 1176 (w),1117 (s), 1087 (m), 1018 (m), 962(m), 859 (m), 791(w). MS (m/z): 468.3([M+H]⁺).

Example 407N(3)-(1-Methyl-1-phenylethyl))-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0ml), Et₃N (60 μl, 0.43 mmol), BOP reagent (159 mg, 0.36 mmol) and2-phenylprop-2-ylamine (48 mg, 0.36 mmol) furnished the title compound(107 mg, 66%). M.P.: 114-117° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.82-7.73 (m, 1H); 7.66-7.54 (m, 2H); 7.39 (d, J=7.8, 2H); 7.35-7.26 (m,3H); 7.22-7.15 (m, 1H): 2.95 (hr. d, J=2.7, 1H); 2.12-2.05 (m, 1H);1.85-1.74 (m, 1H); 1.65 (d, J=9.6, 2H); 1.30-0.95 (m, 1H); 0.90 (s, 3H);0.85 (s, 3H); 0.71 (s, 3H). IR (cm⁻¹, KBr): 3390 (m), 2973 (m), 2931(m), 2871 (m), 1605 (w), 1583 (w), 1542 (s), 1526(s), 1494 (s), 1446(m), 1392 (w), 1378 (w), 1360 (w), 1319 (w), 1268 (m), 1108 (m), 928(m), 870 (m), 766 (m). MS (m/z): 450.0 ([M+]⁺).

Example 408N(3)-tert-Butyl-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (46 μl, 0.33 mmol), BOP reagent (139 mg, 0.31 mmol) andtert-Butylamine (32 mg, 0.45 mmol) furnished the title compound (90 mg,77%). M.P.: 150-154° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.53-7.43 (m,1H); 7.03-6.95 (m, 2H); 6.71 (br. s, 1H); 3.22 (d, J=3.9, 1H); 2.13-2.06(m, 1H); 1.84-1.76 (m, 1H); 1.45 (s, 9H); 1.32-1.24 (m, 2H); 0.97, 0.90,0.78 (3s, 9H). IR (cm⁻¹, KBr): 3402 (s), 3070 (w), 2966 (s), 2873 (m),1671 (s), 1613 (m), 1549 (m), 1500 (s), 1472 (w), 1448 (m), 1390 (m),1.364 (m), 1322 (m), 1268 (s), 1219 (m), 1139 (s), 1116 (m), 1090 (m),1018 (m), 961 (m), 861 (m), 846 (m). MS (m/z): 388.2 ([M+H]⁺).

Example 409 Methyl(2R)-2-[1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamido]-2-phenylethanoate

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (300 mg, 0.90 mmol), DMF (4.0ml), Et₃N (284 μl, 0.33 mmol), BOP reagent (418 mg, 0.94 mmol) and(R)-(−)-2-phenylglycine methylester hydrochloride (272 mg, 1.35 mmol)furnished the title compound (290 mg, 67%). M.P.: 107-109° C. ¹H-NMR (δppm, DMSO-d₆, 300 MHz): 8.42-8.36 (m, 1H); 7.78-7.72 (m, 1H); 7.63-7.56(m, 1H); 7.44-7.28 (m, 6H); 5.64 (d, J=7.5, 1H); 3.65, 3.64 (2s, 3H);3.03 (br. s, 1H); 2.12-2.02 (m, 1H); 1.84-1.76 (m, 1H); 1.26-1.20 (m,1H); 1.12-1.00 (m, 1H); 0.91, 0.88 (2s, 6H); 0.74, 0.70 (2s, 3H). MS(m/z): 480.24 ([M+H]⁺).

Example 410N(3)-[(1R)-Hydroxy-1-phenylethyl]-1-(2,4-difluorophenyl)-7,8,8-trimethyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 192. Example 409 (170 mg, 0.34 mmol), THF (3 ml)and LiBH₄ (15 mg, 0.68 mmol) furnished the title compound (120 mg, 75%).M.P.: 68-70° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.52-7.42 (m, 1H);7.40-7.30 (m, 6H); 7.04-6.94 (m, 2H); 5.26-5.16 (m, 1H), 4.04-3.94 (m,2H); 3.20 (d, J=3.6, 1H); 3.02 (br. s, 1H); 2.13-2.06 (m, 1H); 1.84-1.76(m, 1H); 1.34-1.20 (m, 2H); 0.98, 0.91 (2s, 6H); 0.79, 0.76 (2s, 3H). MS(m/z): 452.17 (M+H⁺).

Example 411(4S,7R)—N(3)-tert-Butyl-1-(2,4-difluorophenyl)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methano-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0ml), Et₃N (45 μl, 0.33 mmol), BOP reagent (139 mg, 0.31 mmol) and2-amino-2-methylpropane (47 μl, 0.45 mmol) furnished the title compound(65 mg, 56%). M.P.: 173-175° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.54-7.44 (m, 1H); 7.04-6.94 (m, 2H); 6.73 (br. s, 1H); 3.22 (d, J=3.6,1H); 2.13-2.06 (m, 1H); 1.85-1.76 (m, 1H); 1.45 (s, 9H); 1.33-1.24 (m,2H); 0.97, 0.90, 0.78 (3s, 9H).

Example 501N(12)-Benzyl-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF (1.0ml), Et₃N (36 μl, 0.26 mmol), BOP reagent (103 mg, 0.23 mmol) andbenzylamine (25 μl, 0.23 mmol) yielded the title compound (40 mg, 33%).M.P.; 164-166° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.60 (s, 1H);7.40-7.22 (m, 8H); 7.20-7.00 (m, 4 H); 5.06 (s, 1H); 4.60 (d, J=6.3,2H); 4.28 (s, 1H); 2.00-1.70 (m, 4H). MS (an/z): 474.0 ([M+H]⁺).

Example 502N(12)-Piperidino-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF (1.0ml), Et₃N (36 μl, 0.26 mmol), BOP reagent (105 mg, 0.24 mmol) and1-aminopiperidine (26 μl, 0.23 mmol) yielded the title compound (40 mg,37%). M.P.: 164-166° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (s, 1H);7.44-7.32 (m, 3H); 7.16-7.05 (m, 4 H); 5.02 (s, 1H); 4.27 (s, 1H); 2.83(br. s, 4H); 2.20-1.70 (m, 8H); 1.41 (br. s, 2H). IR (cm⁻¹, KBr): 2934(s), 2854 (m), 1648 (s), 1551 (m), 1509 (s), 1488 (s), 1441 (s), 1381(m), 1355 (m), 1342 (m), 1146 (m), 1097 (m), 1070 (m), 898 (m), 818 (w).MS (m/z): 467.0 ([M+H]⁺).

Example 503N(12)-Piperidino-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamidehydrochloride

A solution of example 502 (250 mg, 0.53 mmol) in ether (5 ml) wastreated with ether saturated with HCl (10 ml) and maintained at RT for 1hour and the precipitated solid was concentrated to yield the titlecompound (200 mg, 74%). M.P.: 100-110° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 7.61 (s, 1H); 7.58 (br. s, 1H); 7.41 (s, 2H); 7.33 (d, J=7.5, 1H);7.15-7.00 (m, 3H); 5.03 (br. s, 1H); 4.27 (br. s, 1H); 2.86 (br. s, 4H);1.80-1.70 (m, 8H); 1.43 (br. s, 2H).

Example 504N(12)-[(N′-Cyclohexyl-N′-methyl)amino]-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (121 mg, 0.27 mmol) andN-cyclohexyl-N-methyl hydrazine (37 mg, 0.29 mmol) to give the titlecompound (70 mg, 55%). M.P.: 127-132° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.62 (s, 1H); 7.52 (br. s, 1H); 7.42-7.20 (m, 3H); 7.20-7.00 (m, 3H);5.05 (s, 1H); 4.28 (s, 1H); 2.69 (s, 3H); 2.82-2.55 (m, 1H); 1.96 (br.s, 2H); 1.88-1.70 (m, 6H); 1.40-1.00 (m, 6H). IR (cm⁻¹, KBr): 3422 (s),2930 (s), 2854 (s), 1667 (s), 1508 (s), 1474 (s), 1381 (m), 1354 (m),1280 (m), 1248 (w), 1134 (m), 1118 (m), 1083 (m), 1012 (m), 815 (m). MS(m/z): 495.1 ([M+H]⁺).

Example 505N(12)-[N′-(2,4-Dichlorophenyl)-N′-methyl]amino)-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0ml), Et₃N (40 μl, 0.29 mmol), BOP reagent (120 mg, 0.27 mmol) andN-(2,4-dichlorophenyl)-N-methylhydrazine (88 mg, 0.46 mmol) to give thetitle compound (80 mg, 55%). M.P.: 220-223° C. ¹H-NMR (δ ppm, CDCl₃, 300MHz): 8.82 (s, 1H); 7.61 (d, J=1.2, 1H); 7.42-7.24 (m, 6 H); 7.15-7.05(m, 3H); 4.94 (s, 1H); 4.28 (s, 1H); 3.33 (s, 3H); 1.79-1.69 (m, 4H). IR(cm⁻¹, KBr): 3376 (s), 3005 (w), 2964 (m), 2867 (m), 1682 (s), 1546 (m),1500 s), 1471 (s), 1352 (m), 1271 (m), 1241 (m), 1116 (m), 1100 (m),81.1 (m), 759 (m). MS (m/z) 556.9 ([M+H]⁺).

Example 506N(12)-(Adamantan-1yl)-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1ml), Et₃N (40 μl, 0.28 mmol), BOP reagent (121 mg, 0.27 mmol) and1-adamantylamine (43 mg, 0.28 mmol) furnished the title compound (80 mg,59%). M.P.: 120-124° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.60 (s, 1H);7.46-7.31 (m, 3H); 7.20-6.99 (m, 3H); 6.59 (br. s 3H); 5.04 (br. s, 1H);4.26 (br. s, 1H); 2.12 (br. s, 9H); 1.90-1.54 (m, 10H). IR (cm⁻¹, KBr):3396 (m), 2906 (s), 2849 (s), 1670 (s), 1548 (s), 1537 (s), 1508 (s),1483 (s), 1457 (m), 1356 (m), 127.9 (w), 1167 (m), 1072 (m), 818 (m). MS(m/z): 540.2 (100, [M+Na]⁺), 518.2 (25, [M+H]⁺).

Example 507N12-(1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl)-10-(2,4-dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2(7),3,5,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0ml), Et₃N (40 μl, 0.28 mmol), BOP reagent (120 mg, 0.27 mmol) and1S,2endo-amino-1,3,3-trimethyl-bicyclo[2.2.1]heptane (43 mg, 0.28 mmol)furnished the title compound (95 mg, 70%). M.P.: 82-85° C. ¹H-NMR (δppm, CDCl₃, 300 MHz): 7.60 (br. s, 1H), 7.43-7.07 (m, 6H); 6.92 (d,J=7.8, 1H); 5.04 (br. s, 1H); 4.29 (br. s, 1H); 3.77 (br. s, 1H);1.92-1.58 (m, 8H); 1.42-0.76 (m, 12H).

Example 508N12-(1-Methyl-1-phenylethyl)-10-(2,4,dichlorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0ml), Et₃N (41 μl, 0.28 mmol), BOP reagent (120 mg, 0.27 mmol) andα,α-dimethylbenzylamine (56 mg, 0.41 mmol) furnished the title compound(70 mg, 53%), M.P.: 190° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.61 (br. s,1H); 7.45-7.05 (m, 12H); 4.98 (br. s, 1H); 4.26 (br. s. 1H); 1.80 (s,3H); 1.77 (s, 3H); 1.75-1.58 (m, 4H).

Example 509N12-(1-Methyl-1-phenylethyl)-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.2.0^(2,7).0^(9,13)]pentadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 25 (100 mg, 0.28 mmol), DMF (1.0ml), Et₃N (44 μl, 0.31 mmol), BOP reagent (131 mg, 0.29 mmol) andα,α-dimethylbenzylamine (58 mg, 0.42 mmol) furnished the title compound(78 mg, 58%). M.P.: 175-178° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz):7.64-7.54 (m, 1H); 7.43 (d, J=7.5, 2H); 7.35-7.02 (m, 10H); 4.98 (br. s,1H); 4.35 (br. s, 1H); 1.81, 1.77 (2s, 6H); 1.80-1.68 (m, 4H). IR (cm⁻¹,KBr): 3403 (s), 3077 (m), 2961 (m), 2973 (m), 1665 (s), 1609 (m), 1526(s), 1493 (s), 1471 (m), 1446 (m), 1383 (w), 1.361 (w), 1328 (w), 1269(m), 1256 (m), 1160 (m), 1146 (m), 1095 (m), 846 (m), 758 (m), 699 (m).MS (m/z); 470.2 ([M+H]⁺).

Example 601N(12)-Benzyl-16-(4-chlorophenyl)-10-(2,4-dichlorophenyl)-15,17-dioxo-10,11,16-triazapentacyclo[6.5.5.0^(2,7).0^(9,13). 0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 26 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (49 μl, 0.35 mmol), BOP reagent (130 mg, 0.29 mmol) andα,α-dimethylbenzylamine (47 mg, 0.35 mmol) furnished the title compound(90 mg, 67%). M.P.: 84-87° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.92-7.79(m, 2H), 7.71-7.61 (m, 1H); 7.41-7.15 (m, 8H); 6.98-6.90 (m, 2H); 4.43(br. s, 1H); 4.36 (s, 1H); 2.88 (d, J=7.8, 1H); 2.70 (d, J=7.5, 1H);1.66, 1.64 (2s, 6H); IR (cm⁻¹, KBr): 3404 (m), 2974 (w), 2933 (w), 2867(w), 1679 (s), 1608 (w), 1522 (s), 1507 (m), 1447 (m), 1382 (w), 1362(w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 1029 (w), 1006(w), 965 (m), 847 (m), 786 (w), 761(m). MS (m/z): 456.2 [M+H]⁺); 338.1(100).

Example 602

N(12)-Piperidino-16-(4-chlorophenyl)-10-(2,4-dichlorophenyl)-15,17-dioxo-10,11,16-triazapentacyclo[6.5.5.0^(2,7).0^(9,13). 0^(14,18)]octadeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 26 (100 mg, 0.18 mmol), DMF (1.0ml), Et₃N (30 μl, 0.20 mmol), BOP reagent (85 mg, 0.19 mmol) and1-aminopiperidine (22 μl, 0.20 mmol) afforded the title compound (35 mg,31%). M.P.: 150° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66 (s, 1H); 7.60(br. s, 1H); 7.46-7.40 (m, 3H); 7.26-7.17 (m, 5H); 6.44 (d, J=8.4, 2H);5.58 (d, J=3.3, 1H); 4.81 (d, J=1H); 3.58 (dd, J=8.4, 3.3, 1H); 3.46(dd, J=8.1, 3.3, 1H); 2.89-1.20 (m, 10H). IR (cm⁻¹, KBr): MS (m/z):646.2 ([M+H]⁺).

Example 701

N12-Benzyl-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (49 μl, 0.35 mmol), BOP reagent (130 mg, 0.29 mmol) and benzylamine (32 μl, 0.29 mmol) furnished the title compound (90 mg, 71%).M.P.: 65-67° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 8.70 (br. s, 1H);7.85-7.75 (m, 1H); 7.65 (t, J=9.0, 1H); 7.23-7.30 (m, 8H); 6.95 (br. d,J=2.9, 2H); 4.39-4.47 (m, 4H); 2.8.9 (d, J=7.5, 1H); 2.73 (d, J=7.5,1H). IR (cm⁻¹, KBr): 3404 (m), 3063 (w), 2974 (w), 2933 (w), 2867 (w),1679 (s), 1608 (w), 1522 (s), 1507 (s), 1447 (m), 1382 (w), 1362 (w),1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 965 (m), 847 (w), 761(m). MS (m/z): 428.2 [M+H]⁺.

Example 702N(12)-tert-Butyl-10-(2,4-difluorophenyl)-10,11-diazatetracyclo[6.5.1.0^(2,7).0^(9,13)]tetradeca-2,4,6,9(13),11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0ml), Et₃N (49 μl, 0.35 mmol), BOP reagent (143 mg, 0.32 mmol) and2-amino-2-methylpropane (31 μl, 0.29 mmol) furnished the title compound(91 mg, 78%). M.P.: 59° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.72-7.62 (m,1H); 7.41 (d, J=5.7, 1H); 7.32-7.26 (m, 1H); 7.07-6.92 (m, 4H); 6.65(br. s, 1H); 4.62 (br. s, 1H); 4.29 (br. s, 1H); 2.96 (d, J=7.5, 1H);2.82 (d, J=7.5, 1H); 1.43 (s, 9H).

Example 801N5-(tert-Butyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.2.0^(2,6)]undeca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0ml), Et₃N (54 μl, 0.35 mmol), BOP reagent (159 mg, 0.36 mmol) and2-amino-2-methylpropane (34 0.32 mmol) furnished the title compound (96mg, 81%). M.P.: 105-108° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.62-7.54(m, 1H): 7.08-6.99 (m, 2H); 6.82 (br. s, 1H); 3.83 (br. s, 1H); 3.11(br. s, 1H); 1.75 (d, J=6.6, 4H); 1.52-1.26 (m, 4H); 1.47 (s, 9H).

Example 802N(5)-(tert-Pentyl)-3-(2,4-difluorophenyl)-3,4-diazatricyclo[5.2.2.0^(2,6)]undeca-2(6),4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to thatdescribed for example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0ml), Et₃N (54 μl, 0.39 mmol), BOP reagent (159 mg, 0.36 mmol) andtert-amyl amine (38 μl, 0.32 mmol) furnished the title compound (81 mg,66%). M.P.: 102-105° C. ¹H-NMR (δ ppm, CDCl₃, 300 MHz): 7.66-7.54 (m,1H); 7.10-6.96 (m, 2H); 6.74 (br. s, 1H); 3.82 (br. s, 1H); 3.13 (br. s,1H); 1.89-1.70 (m, 6H); 1.42 (s, 6H); 1.48-1.43 (m, 2H); 1.30-1.20 (m,2H); 0.92 (t, J=7.2, 3H). MS (m/z): 374.1 ([M+H]⁺).

Protocols

I. In vitro Protocol for Rat CB1 Receptor Binding Using Brain Membrane

In this assay, [³H]SR141716A(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide)was used to bind the CB1 receptor present in a rat brain membranepreparation which can be displaced by unlabeled ligands having affinityto the CB1 receptor.

The assay was performed according to the modified method of Thomas etal., 1998 (JET 285: 285-292). The total reaction mixture (250 ml)contained Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5% BSA) orunlabeled SR141716A. (1 mM) or test samples (1 mM), [³H] SR141716A (2nM) and 100 mg of rat brain membrane. The non-specific binding wasdefined by 1 mM of SR141716A. The assay mixture was incubated at 37° C.for 1 hour. The reaction was then stopped by rapid filtration undervacuum using Whatman GF/B-96 micro filter plate. A scintillationcocktail was added and radioactive counts were measured using a Topcountbeta scintillation counter.

The standard and test sample dilutions were made in an assay buffercontaining either ethanol or DMSO at a final concentration of 1%.

The percent (%) displacement by a test ligand was calculated bycomparing the specific bound values. The results of the assay are shownin Table II below.

II. Protocol for In vitro Assay Using hCB1-CHO Membranes

In this assay, [³H]-CP-55,940((−)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol)was used as the radioligand to bind human CB1 receptors expressed on themembranes from CHO cells (the hCB1-CHO cell line was generated in-house)which can be displaced by unlabeled ligands having affinity to the CB1receptor.

The assay was performed according to the modified method of Ross et al.,1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in atotal volume of 200 μl in PEI (Poly(ethyleneimine)) (0.2%) precoatedMillipore GFB (Glass Fibre-B) filter plates. 1 mM stocks of testcompounds were prepared in DMSO and tested at a final concentration of300 nM. The non-specific binding was determined by 0.5 μM CP-55, 940.The total reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mMMgCl₂, 1 mM EDTA, pH 7.4 with 0.1% BSA), unlabelled CP-55, 940 (0.5 μM)or test samples, [³H]-CP-55, 940 (0.75 nM) and 50 μg of human CB1receptor preparation. The assay mixture (with or without the testcompound) was incubated at 37° C. for 1 hour. The reaction was stoppedby rapid filtration under vacuum and the radioactivity on the filterswas measured by liquid scintillation counting. The results of the assayare shown in Table II below.

III. In vitro Protocol for Rat CB2 Receptor Binding Using SpleenMembrane

In this assay, [³H]CP55,940 was used to bind the CB2 receptor present ina rat spleen membrane preparation which can be displaced by unlabeledligands having affinity to the CB2 receptor.

The assay was performed according to the modified method ofRinaldi-Carmona et al., 1998 (WET 284: 644-650). The total reactionmixture (250 ml) contained Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5%BSA) or unlabeled SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methyl-benzyl)-pyrazole-3-carboxamide])(1 mM) or test samples (300 nM), [³H]CP55,940 (1 nM) and 100 mg of ratbrain membrane. The non-specific binding was defined by 1 mM of SR144528. The assay mixture was incubated at 37° C. for 1 hour. Thereaction was then stopped by rapid filtration under vacuum using aWhatman GF/B-96 micro filter plate. A scintillation cocktail was addedand radioactive counts were measured using a Topcount beta scintillationcounter.

The standard and test sample dilutions were made in an assay buffercontaining either ethanol or DMSO at a final concentration of 1%.

The percent (%) displacement by a test ligand was calculated bycomparing the specific bound values. The results of the assay are shownin. Table II below.

IV. Protocol for In vitro Assay Using hCB2-CHO Membranes:

In this assay, [³H]-CP-55,940 was used as the radioligand to bind humanCB2 receptor expressed on the membranes from CHOcells (hCB2-CHO cellline was generated in-house) which can be displaced by unlabeled ligandshaving affinity to the CB2 receptor.

The assay was performed according to the modified method of Ross et al.,1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in atotal volume of 200 μl in PEI (0.2%) precoated Millipore GFB filterplates. 1 mM stocks of test compounds were prepared in DMSO and testedat a final concentration of 300 nM. The non-specific binding wasdetermined by 0.5 μM CP-55, 940. The total reaction mixture contained.Tris-BSA buffer (50 mM Tris, 5 mM MgCl₂, 1 mM EDTA, pH 7.4 with 0.1%BSA), unlabelled CP-55, 940 (0.5 μM) or test samples, [³H]-CP-55, 940(0.75 nM) and 25-50 μg of human CB2 receptor preparation. The assaymixture (with or without the test compound) was incubated at 30° C. for1 hour. The reaction was stopped by rapid filtration under vacuum andthe radioactivity on the filters was measured by liquid scintillationcounting.

The percent (%) displacement by a test ligand was calculated bycomparing the specific bound values. The results of the assay are shownin Table II below.

V. Neuropathic Hyperalgesia Model—Partial Sciatic Nerve Ligation(Seltzer's Model)

This protocol was performed with the compound of Example 294 at 0.01,0.1, 0.3, and 1 mg/kg (I.P.), and gabapentin at 100 mg/kg (I.P.) toevaluate the ability of the compound of Example 294 in reducingneuropathic hyperalgesia. The Seltzer method is also generally describedin Seltzer et al., Pain 1990, 43:205-18.

-   -   1. Rats were anesthetised using ketamine/xylazine (40/5        mg/kg/ml, i.p.). After induction of anaesthesia, the left thigh        was shaved and cleaned.    -   2. The left sciatic nerve was exposed at mid thigh level through        a small incision.    -   3. The nerve was cleared from adhering muscle tissue.    -   4. One half of the nerve thickness was tightly ligated just        after the bifurcation of common sciatic nerve using 7.0 silk        sutures.    -   5. The wound was closed with muscle and skin sutures and        povidone was applied.    -   6. The animals were allowed to recover for 12 to 15 days post        ligation.    -   7. Mechanical hyperalgesia was examined in the model of rat        neuropathic pain, using the paw pressure technique (Ugo Basile        Analgesymeter, Cat. No. 37215, Comerio, Italy).    -   8. Paw withdrawal thresholds were recorded for both the        ipsilateral and the contralateral hind paws before (predose) and        0.5 and 1 hour after drug or vehicle administration (postdose).    -   9. The cut-off was set at 150 g pressure and the endpoint was        taken as paw withdrawal or vocalization.        Data Analysis:

The threshold withdrawal latency (naïve, predose & postdose) values arerepresented as mean±SEM. See Walker K M, Urban L A, Medhurst S J, PatelS, Panesar M, Fox A J and Mcintyre P., “The VR1 antagonist capsazepinereverses mechanical hyperalgesia in models of inflammatory andneuropathic pain”, J. Pharmacol. Expt. Ther. 304: 56-62, 2003. Thepercent reversal of neuropathic mechanical hyperalgesia was calculatedfrom withdrawal threshold latency values according to the followingformula:

${\%\mspace{14mu}{Reversal}} = {\frac{{{Ipsilateral}\mspace{14mu}{postdose}} - {{Ipsilateral}\mspace{14mu}{predose}}}{{{Contralateral}\mspace{14mu}{predose}} - {{Ipsilateral}\mspace{14mu}{predose}}} \times 100\%}$

Data statistical analyses were performed on the percent reversal valuesby one-way ANOVA followed by post hoc Tukey's test using GraphPad Prismsoftware.

The results are shown in FIG. 1. 1 mg/kg of the compound of Example 294significantly reversed neuropathic hyperalgesia in this model.

VI. Chronic Constriction Injury (CCI) to Sciatic Nerve Model (CCI Model)

This protocol was performed with the compound of Example 294 at 0.1mg/kg (p.o), and gabapentin at 100 mg/kg (i.p.) to evaluate the abilityof the compound of Example 294 in reducing neuropathic hyperalgesia.This method is also generally described in Miletic G and Miletic V,“Long-term changes in sciatic-evoked A-fiber dorsal horn fieldpotentials accompany loose ligation of the sciatic nerve in rats,” Pain84:353-359, 2000.

-   1. Rats were anesthetised using ketamine/xylazine (40/5 mg/kg,    i.p.). After induction of anaesthesia, the left thigh was shaved and    cleaned.-   2. The left sciatic nerve was exposed at mid thigh level through    small incision.-   3. The nerve was cleared from adhering muscle tissue.-   4. Four loose ligatures of Ethicon 4-0 chromic gut (Johnson &    Johnson) at 1 mm space were placed around the nerve after the    bifurcation of common sciatic nerve.-   5. The wound was closed with muscle and skin sutures & povidone was    applied.-   6. The animals were used for experiment after 7 days of ligation.-   7. Mechanical hyperalgesia was examined in the model of rat    neuropathic pain, using the paw pressure technique (Ugo Basile    Analgesymeter, Cat. No. 37215, Comerio, Italy).-   8. Paw withdrawal thresholds were recorded for both the ipsilateral    and the contralateral hind paws before (predose) and 0.5 and 1 hour    after drug or vehicle administration (postdose).-   9. The cut-off was set at 150 g pressure and the endpoint was taken    as paw withdrawal or vocalization.    Data analysis was performed as described in protocol V. The results    are shown in FIG. 2.    VII. Tail-Flick Analgesia Testing in Mice

Tail flick latency (basal) was measured in naive mice at 55° C. treatedwith vehicle, WIN 55212-2 (a CB1 receptor agonist) (3 mg/kg i.p.), orExample 294 (0.3, 1, or 3 mg/kg i.p.) using a water bath (Julabo,Germany). See Murielle R., Barth F., Congy C., Martinez S., Oustric D.,Perio A., Poncelet M., Maruani J., Arnone M., Finance O., Soubrie P.,and Le'Fur G., “SR147778(5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide),a New Potent and Selective Antagonist of the CB1 CannabinoidReceptor:Biochemical and Pharmacological Characterization,” J.Pharmacol. Exp. Ther., 310: 905-914, 2004. The mice were givenintraperitoneal (i.p.) injection of vehicle, standard or test drug.Analgesia was assessed by measuring tail flick latency (reaction) at 1,3, 6, 12, and 18 hours post dosing. The cut-off latency was set at 10Seconds and the endpoint was taken as tail flick response of the tail.

Data Analysis

The tail flick latency (basal & reaction) values were represented asmean± SEM. Maximum analgesia (% MPE) was calculated according to thefollowing formula:

${\%\mspace{14mu}{Maximum}\mspace{14mu}{Possible}\mspace{14mu}{analgesic}\mspace{14mu}{effect}} = {\frac{\left( {{{Reaction}\mspace{14mu}{latency}} - {{Basal}\mspace{14mu}{latency}}} \right)}{\left( {{{Cut}\text{-}{off}\mspace{14mu}{latency}} - {{Basal}\mspace{14mu}{latency}}} \right)} \times 100}$

Data analyses were performed on the percent MPE values by one-way ANOVAfollowed by post hoc Tukey's test. The results are shown in FIG. 3.

VIII. Protocol for GTPγS Binding, Assay (CB1 Functional Assay in RatCerebellar Membrane)

In this GTPγS binding assay, total, basal and nonspecific binding weredetermined. See Griffin G., Atkinson P. J., Showalter V. M., Martin. B.R. and Abood M. E., “Evaluation of cannabinoid receptor agonists andantagonists using the Guanosine-5′-O-(3-(³⁵S)thio)-triphosphate bindingassay in rat cerebellar membranes,” J Pharmacol Exp Ther 285: 553-560,1998. Three wells for total binding, three wells for basal binding, andthree wells for nonspecific binding at 0.2 nM concentration ofradioligand were used. Basal binding was defined by 50 μM GDP (Guanosinediphosphate) and non-specific binding was defined by 10 μM unlabeledGTPγS. 10 μg rat cerebellum membrane, 50 μM of GDP, WIN-55212-2 or testcompound (1 μM or 300 nM), 10 μM unlabeled GTPγS, and 0.2 nM of[³⁵S]GTPγS were added into a 96 well plate and the final volume of thereaction mixture was made with GTPγS buffer (50 mM Tris, 3 mM anhydrousMgCl₂, 0.2 mM EGTA and 100 mM NaCl pH 7.4) to 200 μl. The plates wereincubated at 30° C. for 1 hour. Then the reaction was stopped byfiltration using a Whatman GF/B-96 microfilter plate. Three washingswere given using Tris-HCl. The radioactivity bound to the brain membranewas retained on the filter disks to which scintillation fluid was added(Microscint PS). Then plates were read for radioactive counts using aBeta Liquid Scintillation Counter (Packard Instruments, IL, USA).

The rat cerebellar brain membrane was prepared as follow:

-   -   1. Sacrifice the rat and take out the whole brain and separate        cerebellum as fast as possible and keep it on ice.    -   2. Take the weight of the cerebellum and homogenize in 30 ml of        homogenizing buffer (50 mM Tris-HCL containing 1 mM EDTA and 5%        sucrose, pH 7.5) using homogenizer in cold condition.    -   3. Centrifuge the homogenized cerebellum at 18000 rpm (38000 g)        for 15 min at 4° C.    -   4. Resuspend the pellet in 5 ml 50 mM Tris-HCL containing 1 mM        EDTA and keep it on ice for 30 min.    -   5. Pass the membrane through insulin syringe to ensure uniform        suspension.    -   6. Centrifuge the membrane at 18000 rpm at 4° C. for 20 mM.    -   7. Reconstitute the pellet in 3 ml of GTPγS buffer and estimate        the protein by BCA assay and store the membrane in aliquots of        1000 μg of protein.        CB1 Agonist and Antagonist Activity Screening Assay

The test compounds were screened at a final concentration of 1 μM or 300nM in the absence and presence of 1 μM of WIN 55,212-2 in the samemanner as described in the GTPγS binding assay.

An agonist will stimulate the GTPγS binding over the basal.

An antagonist will inhibit the WIN-55212-2 (CB1 agonist) and inducestimulation of GTPγS binding without significantly altering the basalbinding.

An inverse agonist will decrease the basal. GTPγS binding and/or producemore than 100% inhibition of the agonist (WIN-55212-2) inducedstimulation.

A partial agonist normally produces only partial stimulation over basaland also partially inhibits agonist (WIN-55212-2) induced stimulation ofGTPγS binding.

Data Analysis:

The percent stimulation of GTPγS binding by each test compound at 1 μMor 300 nM concentration in the absence and presence of 1 μM WIN 55,212-2was calculated by comparing it with basal specific bound (Basalbinding—Non Specific binding) values.

The results are shown in Table III below.

IX. Assay for Determining Agonist and Antagonist Activity to CB1 and CB2Receptors

1. Antagonism of CB1/CB2 Receptors Expressed in CHO Cells.

h-CB1/CHO or h-CB2/CHO cells were grown in HAM's F12 DMEM medium (Sigma)with 10% FBS (Hyclone), 1% penicillin-streptomycin solution and 400μg/ml of G418 (Sigma). 5000 cells were seeded per well in a 96 wellplate and incubated for 24 hours at 37° C. in 5% CO₂. On the day ofassay, cells were washed with warm Krebs buffer containing 0.1% fattyacid free (FAF) BSA (Sigma) and re-suspended in the same buffercontaining 1 mM IBMX. Test antagonist or reference compound (AM 251(1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide)for CB1 and SR 144528 for CB2) diluted in FAFBSA+IBMX+Krebs buffer wasadded to the cells and incubated for 10 minutes at room temperature. CP55,940 (30 nM final concentration for CB1 testing and 10 nM of the samefor CB2 testing) was added to cells followed by forskolin (10 μM finalconcentration) and incubated for 30 minutes at room temperature. At theend of incubation, cells were lysed using lysis reagent from the cAMPestimation kit and cAMP was quantitated by the chemiluminescence methoddescribed in the manufacturer's instructions (DiscoveRX). EC₅₀ valueswere calculated from dose response curves by nonlinear regressionanalysis using PRISM software.

2. Agonism of CB1/CB2 Receptors Expressed in CHO Cells

h-CB1/CHO or h-CB2/CHO cells were grown in HAM's F12 DMEM medium (Sigma)with 10% FBS (Hyclone), 1% penicillin-streptomycin solution and 400μg/ml of G418 (Sigma). 5000 cells were seeded per well in a 96 wellplate and incubated for 24 hours at 37° C. in 5% CO₂. On the day ofassay, cells were washed with warm Krebs Buffer containing 0.1% fattyacid free (FAF) BSA (Sigma) and re-suspended in the same buffercontaining 1 mM IBMX. Test compound or CP 55,940 as a reference compound(30 nM: final concentration for CB1 testing and 10 nM of the same forCB2 testing) diluted in FFB+IBMX+Krebs buffer was added to the cellsfollowed by forskolin addition (10 uM final concentration) and incubatedfor 30 minutes at room temperature. At the end of incubation, cells werelysed using lysis reagent from the cAMP estimation kit and cAMP wasquantitated by chemiluminescence method described in the manufacturer'sinstructions (DiscoveRX). EC₅₀ values were calculated from dose responsecurves by nonlinear regression analysis using PRISM software. Theresults are shown in Table IV below.

TABLE II Example % Displacement No. Protocol I Protocol II Protocol IIIProtocol IV 101 28.8 5.75 — 0 102 27.3 18.56 — 0.74 103 22.2 0 — 6.99104 — 5.41 — 20.24 105 — 15.03 — 22.35 106 78.6 15.07 — 75.06 107 97.482.49@1  — — 108 82.5 23.19 — 37.15 109 — 8.36 — 63.05 110 — 37.69 —60.7 111 110.6 32.19 — — 112 59.9 25.76 — — 113 55.9 27.70 — 17.02 114 —25.27 — 31.67 115 — 39.62 — — 116 24.9 1.85 — — 117 — 80.08 59.8 — 118 —45.43 — 61.23 119 — 89.21 85.2 — 120 30.4 15.43 — 9.18 121 65.4 3.01 —29.8  122* 66.4 80.08 — — 123 89.0 — — 47.63 124 80.1 66.41 — — 125 52.722.07 — 5.04 126 118.0 — — — 127 85.3 — — — 128 83 37.28 — — 129 65.219.78 — 62.85 130 60.6 12.32 — — 131 85.2 22.78 — 10.84 132 64.5 16.09 —3.94 133 59.7 65.9@1 — — 134 89.6 63.68 — — 135 20.5 10.05 — 6.48 13631.3 1.01 — 15.44 137 76.7 50.75 — — 138 — 79.4 — 67.99 139 62.4 — — —140 50.4 57.85 — 15.79 141 17 — — — 142 25 — — 9.86 143 102.2 81.7 — —144 — 40.13 — 69.24 145 — 54.01 — 75.88 146 — 60.51 — 68.16 147 — 39.9 —37.14 148 — 75.56 — 79.21 149 — 82.67 — — 150 — 78.72 — — 151 — 92.43 —69.16 152 — 84.24 — 60.26 153 — 96.92 — 99.46 154 — 96.1 — 70.19 155 —96.65 — 72.38 156 — 86.37 — 89.29 157 — 84.84 — 88.5 158 — 70.12 — 95.4 158a — — — 94.62 159 — 81.31 — 97.65 160 10.0 7.32 — 20.75 161 27.922.54 — 39.35 162 38.9 9.52 — 33.8 163 — 17.3 — 14.46 164 8.2 19.15 —13.15 165 14.2 6.64 — 45.27 166 —  8.7@1 — 18.16 167 61.3 44.72 — 24.59168 37 11.47 — — 169 19 29.65 — — 170 40.0 29.49 — 27.16 171 0 19.37 —0.56 172 59.2 — — 25.11 173 67.1 — — — 174 76.4 21.69 — 22.53 175 6625.7 — 18.48 176 65.6 39.34 — 30.48 177 75.6 — — 15.26 178 47 — — 6.04179 48 30.88 — 18.21 180 40.6 28.65 — 13.19 181 16.4 — — — 182 39.919.35 — 12.78 183 45.9 17.24 — 18.23 184 41 3.24 — 8.76 185 — 51.98 —60.66 186 17.2 16.13 — 59.06 187 6.0 15.66 — 0.7 188 19.5 12.5 — 36.01 189a 7 21.2 — 0.81  189b 3 24.03 — 2.56  190a — — — 0  190b — 100 —96.07 191 — 78.71 — 62.18 192 — — — 19.12 201 9.0 24.91 — 19.79 202 28.216.53 — 70.13 203 −10.4 56.51 — — 204 −10.3 23.84 — 10.53 205 −12.722.27 — 15.93 206 27.4 15.15 — 71.87 207 −1.2 9.39 — — 208 −1.2 — — 0209 23.5 30.35 — 50.52 210 12.6 11.58 — 17.69 211 27.6 19.47 — 80.4 21268.4 72.25 — — 213 48.5 17.57 — 71.8 214 10.1 9.01 — 41.3 215 — 1.38 — —216 32.2 34.03 — 20.74 217 20.5 38.55 — 10.74 218 29.9 44.41 — — 21933.7 59.57 — — 220 29.5 17.92 — 25.29 221 68.6 0 — 75.66 222 39.4 — —15.72 223 52.1 21.5 — 59.5 224 81.6 42.62 — — 225 31.1 46.8 — — 226 38.472.08 — — 227 25.3 3.51 — — 228 16.1 0 — 9.4 229 47.1 0.01 — 24.6 23087.2 72.54@ 1 μm — — 231 31.9 30.79 — — 232 49.7 1.15 — 13.76 233 73.210.79 — 46.22 234 36.3 3.33 — 10.64 235 46.8 80.94 — — 236 75.5 55.25 —— 237 65.6 80.77 — — 238 73.9 24.52 — — 239 23.5 8.09 — 77.12 240 1.5 0— 7.98 241 92.5 87.5 — — 242 — 84.89 — — 243 23.5 1.74 — — 244 — 1.7 —88.35 245 — 30.82 — 84.79 246 46.0 — — 30.44 247 — 22.75 — 79.12 248 —40.11 — — 249 47.7 — — — 250 27.1 6.46 — 27.93 251 42.3 20.93 — 60.18252 99.8 74.52 — — 253 63.0 43.16 — — 254 9.1 — — — 255 23.9 — — — 25663.3 7.71 — — 257 73.5 30.69 — 83.94 258 — 61.78 — — 259 18.3 2.72 —33.33 260 84.4 30.22 — 80.22 261 — 34.15 — — 262 −1.6 21.54 — 32.58 26369.1 26.73 — 79.04 264 85.6 60.85@ 1 μm — — 265 31.6 25.85 — 70.16 26634.5 23.00 — 61.98 267 90.0 60.43 — — 268 41.0 74.52 — — 269 47.7 57.25— — 270 −14.6 18.04 — 8.62 271 11.7 17.7 — 45.96 272 −4.5 13.99 — 18.37273 −5.9 8.94 — 26.25 274 25.7 7.83 — 35.42 275 38.8 7.02 — 72.28 27625.3 3.97 — 14.11 277 −12.8 5.41 — 22.13 278 — 26.86 — — 279 62.0 44.84— — 280 33.0 40.37 — — 281 — — — 97.11 282 — — — 92.31 283 — 58.84 —94.79 284 13.7 25.15 — 0.9 285 61.9  53.9@1 μm — — 286 — 32.35 — — 287 —36.8 — — 288 — 1.05 — 60.78 289 71.3 40.2 — — 290 80.3 70.03 — — 291 —64.44 — — 292 — 69.79 — — 293 — 51.88 — — 294 110.7 78.08 — — 295 — 93 —100 296 — 94.62 — 95.88 297 — 71.92 — 70.29 298 — 28.07 — 11.25 299 —86.48 — 77.61 300 — 54.93 — 90.14 301 — 82.54 — 82.09 302 — 2.43 — 71.77303 — 9.41 — 89.67 304 — — — — 305 — — — — 306 — 3.56 — 62.9 307 — 26.11— 70.32 308 — 91.26 — 86.58 309 — 92.57 — 98.49 310 — 96.75 — 94.25 311— 69.58 — 94.38 312 — 10.97 — 4.47 313 — 65.99 — 98.17 314 — 23.25 —64.87 315 — 36.78 — 64.23 316 — 13.83 — 66.65 317 — — — 16.92 318 — — —30.99 319 — 88.02 — 86.68 320 — 39.42 — 67.77 321 — 11.78 — 92.91 322 —16.74 — 43.44 323 — 4.25 — 82.49 324 — 7.23 — 88.53 325 — 50.42 — 99.64326 — 73.99 — 99.18 327 — 70.23 — 99.99 328 — 2.00 — 64.39 329 — 11.58 —88.50 330 — — — 64.88 331 — — — 75.26 332 — — — 70.06 333 — — — 100.00334 — — — 100.00  335a — — — 96.49  335b — — — 8.70  336b — — — 26.46401 — 12.04 — — 402 — 16.52 — 2.66 403 — 26.52 — 13.35 404 — 24.34 —23.79 405 — 63.21 — 87.87 406 — 72.49 — 94.3 407 — 87.28 — 88.44 408 —24.93 — 61.92 409 — 85.98 — 65.34 410 — — — 15.5 411 — — — 49.68 50182.5 70.15 — — 502 81.3 52.76 — — 503 81.2 56.25 — — 504 79.7 62.9 — —505 90.6 77.51 — — 506 — 0 — 52.4 507 — 76.33 — 91.7 508 — 95.97 — 67.67509 — 93.35 — 67.18 601 2.8 — — 0.99 602 4.1 — — 16.4 701 — 46.7 — 28.34702 — — — 33.00 802 — 81.33 — 100.00

TABLE III PROTOCOL-VIII % Inhibition of Example Per Se WIN-55212-2 No. %Stimulation induced stimulation 106 −10.0% 65.3% 107 4.0% 71.5% 111 6.1%101.1% 121 16.0% 81.3% 122 1.2% 59.3% 123 13.5% 99.1% 126 −7.9% 104.1%127 18.0% 100.2% 131 −1.7% 86.0% 132 7.2% 89.2% 137 13.0% 76.0% 139−8.5% 109.1% 140 24.9% 71.9% 143 43.1% 45.0% 170 17.5% 80.3% 172 −18.3%115.3% 173 1.3% 99.5% 174 −20.8% 75.5% 177 9.7% 109.1% 178 −0.7% 88.0%179 7.8% 89.7% 180 10.0% 87.9% 183 13.0% 72.5% 184 9.5% 75.9% 212 −13.8%97.4% 221 −16.7% 95.7% 224 5.0% 78.1% 230 42.4% 99.4% 233 −16.3% 79.5%236 8.0% 83.0% 237 7.1% 74.7% 238 0.4% 59.1% 246 0.7% 98.9% 256 −21.5%69.7% 257 −5.1% 48.3% 260 38.0% 78.8% 264 −0.1% 94.5% 268 29.1% 55.3%269 6.0% 91.4% 290 3.8% 35.3% 501 53.7% 40.1% 502 1.8% 91.1% 503 1.5%92.0% 505 15.6% 94.4% Above examples were tested at 1 uM 117 4.4% 55.7%119 46.0% 38.9% 134 −6.0% 58.1% 162 −29.2% 72.0% 241 54.7% 32.9% 24233.4% 22.9% 252 48.2 58.8 253 −9.3% 79.9% 267 12.3% 43.6% 294 102.8%9.8% Above examples were tested at 300 nM

TABLE IV FUNCTIONAL ASSAY DATA Example hCB1 hCB2 No. Agonism AntagonismAgonism Antagonism 106 NT 0% 50.90% 109 NT 61.64% at 10 uM NT 117 18.87nM-IC₅₀ 14.91% NT 119 38.33 nM-IC₅₀ 18.42% at 10 uM NT  122* NT 40.66%at 10 uM NT 134 75.61% at 10 uM 17.53% at 10 uM NT 140 48.88% at 10 uM19.31% at 10 uM NT 149 79.86% at 10 uM 15.98% at 10 uM NT 150  61.1% at10 uM 42.93% at 10 uM NT 186  29.4% at 10 uM    0% at 10 uM  8.51 nMIC₅₀   21% at 10 uM 202    0% at 10 uM    0% at 10 uM 16.79 0 206 NT NT10.52 nM IC₅₀ 15.96% at 10 uM 211  16.87 at 10 uM    0% at 10 uM 40.65nM IC₅₀ 20.33% at 10 uM 212 NT 39.13% at 10 uM NT 213    0% at 10 uM   0% at 10 uM 12.67 nM IC₅₀ 22.05% at 10 uM 219 NT  33.4% at 10 uM NT221    0% at 10 uM    0% at 10 uM 36.43 nM IC₅₀ 30.07% at 10 uM 223 NT   0% at 10 uM  1.49 nM IC₅₀ 24.37% at 10 uM 226 NT 71.03% at 10 uM NT235 NT 59.85% at 10 uM NT 238 NT 55.05% at 10 uM 24.54% at 10 uM 239 NT42.52 nM IC₅₀  64.1% at 10 uM 244    0% at 10 uM 61.52% at 10 uM  5.66nM IC₅₀ 25.33% at 10 uM 245    0% at 10 uM 70.67% at 10 uM 50.42 nM IC₅₀32.91% at 10 uM 247    0% at 10 uM 75.31% at 10 uM  5.44 nM IC₅₀ 29.24%at 10 uM 251   37% at 10 uM    0% at 10 uM 40.24 nM IC₅₀ 40.78% at 10 uM257 0 0  3.7 nM IC₅₀ 37.53% at 10 uM 260 0 0  4.1 nM IC50 34.83% at 10uM 263 16.19% at 10 uM 72.13% at 1 uM  2.5 nM IC₅₀ 27.08% at 10 uM 265NT 23.11 nM IC₅₀ 27.24% at 10 uM 266 12.14% at 10 uM 0   14 nM IC₅₀27.71% at 10 uM 268 50.9% at 1 uM 275 16.42% at 10 uM    0% at 10 uM 4.49 nM IC₅₀ 19.14% at 10 uM 288    0% at 10 uM 55.26% at 10 uM  4.76nM IC₅₀ 17.13% at 10 uM 302   19% at 10 uM NT  9.75 nM IC₅₀    0% at 10uM 303  857 nM IC₅₀    0% at 10 uM  0.61 nM IC₅₀  17.6% at 10 uM 304  55% at 10 uM    0% at 10 uM  0.93 nM IC₅₀ 51.60% at 10 uM 305   20% at10 uM    0% at 10 uM  2.16 nM IC₅₀ 37.45% at 10 uM 306 11.95 nM IC₅₀14.36% at 10 uM 307  0.81 nM IC50 21.64% at 10 uM 314  3.41% at 10 uM   0% at 10 uM  8.52 nM IC₅₀ 22.88% at 10 uM 315 12.59% at 10 uM    1%at 10 uM 0.16-1.76 nM IC₅₀ 16.09% at 10 uM 316 18.53% at 10 uM    2% at10 uM  1.2-4.27 nM IC₅₀ 37.63% at 10 uM 320 29.08% at 10 uM    0% at 10uM 0.76-1.25 nM IC₅₀ 22.48% at 10 uM 323    0% at 10 uM    0% at 10 uM14.12 nM IC₅₀ 18.03% at 10 uM 408 NT 16.05 nM IC₅₀ NT 506 NT    0% at 10uM 80.15% at 10 uM NT = Not tested.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as claimed in the appending claims.

All publications, patents, and patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated herein byreference.

We claim:
 1. A method of treating pain associated with diabeticneuropathy in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of formula(IA):

or an analog thereof, pharmaceutically acceptable salt thereof,pharmaceutically acceptable ester thereof, tautomer thereof,stereoisomer thereof, enantiomer thereof, or diastereomer thereof,wherein each occurrence of R is independently substituted orunsubstituted alkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R¹ is hydrogen; R² is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclic group, substituted or unsubstitutedheteroaryl group, substituted or unsubstituted heteroarylalkyl, orNR³R⁴; or R¹ and R² may be joined together to form an optionallysubstituted piperidinyl R³ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl or substituted or unsubstitutedcycloalkyl and R⁴ is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstituted cycloalkyl; orR³ and R⁴ may be joined together to form an optionally substituted 3 to7 membered saturated or unsaturated cyclic ring, which may optionallyinclude at least two heteroatoms selected from O, NR³ or S; p is 1; andA is

wherein each of the dotted lines in A independently represents anoptional bond, and each occurrence of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, and R¹⁴ is the same or different and selected from hydrogen,substituted or unsubstituted alkyl or substituted or unsubstituted aryl;with the proviso that the compound does not have the formula:

wherein R¹ and R² are as defined above.
 2. The method according to claim1, wherein the compound of Formula (1A) is


3. The method according to claim 1, wherein the compound of formula (IA)is (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 4. The method accordingto claim 1, which comprises administering to the subject apharmaceutical composition comprising a therapeutically effective amountof the compound (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 5. The method accordingto claim 1, wherein the subject is human.
 6. The method according toclaim 3, wherein the subject is human.
 7. The method according to claim4, wherein the subject is human.
 8. A method of treating Alzheimer'sdisease in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of formula(IA):

or an analog thereof, pharmaceutically acceptable salt thereof,pharmaceutically acceptable ester thereof, tautomer thereof,stereoisomer thereof, enantiomer thereof, or diastereomer thereof,wherein each occurrence of R is independently substituted orunsubstituted alkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R¹ is hydrogen; R² is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclic group, substituted or unsubstitutedheteroaryl group, substituted or unsubstituted heteroarylalkyl, orNR³R⁴; or R¹ and R² may be joined together to form an optionallysubstituted piperidinyl R³ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl or substituted or unsubstitutedcycloalkyl and R⁴ is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstituted cycloalkyl; orR³ and R⁴ may be joined together to form an optionally substituted 3 to7 membered saturated or unsaturated cyclic ring, which may optionallyinclude at least two heteroatoms selected from O, NR³ or S; p is 1; andA is

wherein each of the dotted lines in A independently represents anoptional bond, and each occurrence of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, and R¹⁴ is the same or different and selected from hydrogen,substituted or unsubstituted alkyl or substituted or unsubstituted aryl;with the proviso that the compound does not have the formula:

wherein R¹ and R² are as defined above.
 9. The method according to claim8, wherein the compound of Formula (1A) is


10. The method according to claim 8, wherein the compound of formula(IA) is (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 8, which comprises administering to the subject apharmaceutical composition comprising a therapeutically effective amountof the compound (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 8, wherein the subject is human.
 13. The method according toclaim 10, wherein the subject is human.
 14. The method according toclaim 11, wherein the subject is human.
 15. A method of treatingpsoriasis in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of a compound of formula(IA):

or an analog thereof, pharmaceutically acceptable salt thereof,pharmaceutically acceptable ester thereof, tautomer thereof,stereoisomer thereof, enantiomer thereof, or diastereomer thereof,wherein each occurrence of R is independently substituted orunsubstituted alkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R¹ is hydrogen; R² is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heterocyclic group, substituted or unsubstitutedheteroaryl group, substituted or unsubstituted heteroarylalkyl, orNR³R⁴; or R¹ and R² may be joined together to form an optionallysubstituted piperidinyl R³ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl or substituted or unsubstitutedcycloalkyl and R⁴ is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstituted cycloalkyl; orR³ and R⁴ may be joined together to form an optionally substituted 3 to7 membered saturated or unsaturated cyclic ring, which may optionallyinclude at least two heteroatoms selected from O, NR³ or S; p is 1; andA is

wherein each of the dotted lines in A independently represents anoptional bond, and each occurrence of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, and R¹⁴ is the same or different and selected from hydrogen,substituted or unsubstituted alkyl or substituted or unsubstituted aryl;with the proviso that the compound does not have the formula:

wherein R¹ and R² are as defined above.
 16. The method according toclaim 15, wherein the compound of Formula (1A) is


17. The method according to claim 15, wherein the compound of formula(IA) is (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 15, which comprises administering to the subject apharmaceutical composition comprising a therapeutically effective amountof the compound (4S,7R)N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 15, wherein the subject is human
 20. The method according toclaim 17, wherein the subject is human.
 21. The method according toclaim 18, wherein the subject is human.